Fused azabicyclic compounds that inhibit vanilloid receptor subtype 1(VR1) receptor

ABSTRACT

Compounds of formula (I) 
                         
are novel VR1 antagonists that are useful in treating pain, inflammatory thermal hyperalgesia, urinary incontinence and bladder overactivity, wherein X 1 , X 2 , X 3 , X 4 , X 5 , R 5 , R 6 , R 7 , R 8a , R 8b , R 9 , Z 1 , Z 2 , and L are defined in the description.

This is a divisional of U.S. patent application Ser. No. 10/364,210,filed Feb. 11, 2003, now U.S. Pat. No. 7,074,805, incorporated herein byreference, and which claims priority from U.S. Provisional ApplicationSer. No. 60/358,220 filed on Feb. 20, 2002.

TECHNICAL BACKGROUND

The present invention relates to compounds of formula (I), which areuseful for treating disorders caused by or exacerbated by vanilloidreceptor activity, pharmaceutical compositions containing compounds offormula (I) and are useful in treating pain, bladder overactivity, andurinary incontinence.

BACKGROUND OF INVENTION

Nociceptors are primary sensory afferent (C and Aδ fibers) neurons thatare activated by a wide variety of noxious stimuli including chemical,mechanical, thermal, and proton (pH <6) modalities. The lipophillicvanilloid, capsaicin, activates primary sensory fibers via a specificcell surface capsaicin receptor, cloned as VR1. The intradermaladministration of capsaicin is characterized by an initial burning orhot sensation followed by a prolonged period of analgesia. The analgesiccomponent of VR1 receptor activation is thought to be mediated by acapsaicin-induced desensitization of the primary sensory afferentterminal. Thus, the long lasting anti-nociceptive effects of capsaicinhas prompted the clinical use of capsaicin analogs as analgesic agents.Further, capsazepine, a capsaicin receptor antagonist can reduceinflammation-induced hyperalgesia in animal models. VR1 receptors arealso localized on sensory afferents which innervate the bladder.Capsaicin or resiniferatoxin has been shown to ameliorate incontinencesymptoms upon injection into the bladder.

The VR1 receptor has been called a “polymodal detector” of noxiousstimuli since it can be activated in several ways. The receptor channelis activated by capsaicin and other vanilloids and thus is classified asa ligand-gated ion channel. VR1 receptor activation by capsaicin can beblocked by the competitive VR1 receptor antagonist, capsazepine. Thechannel can also be activated by protons. Under mildly acidic conditions(pH 6-7), the affinity of capsaicin for the receptor is increased,whereas at pH <6, direct activation of the channel occurs. In addition,when membrane temperature reaches 43° C., the channel is opened. Thusheat can directly gate the channel in the absence of ligand. Thecapsaicin analog, capsazepine, which is a competitive antagonist ofcapsaicin, blocks activation of the channel in response to capsaicin,acid, or heat.

The channel is a nonspecific cation conductor. Both extracellular sodiumand calcium enter through the channel pore, resulting in cell membranedepolarization. This depolarization increases neuronal excitability,leading to action potential firing and transmission of a noxious nerveimpulse to the spinal cord. In addition, depolarization of theperipheral terminal can lead to release of inflammatory peptides suchas, but not limited to, substance P and CGRP, leading to enhancedperipheral sensitization of tissue.

Recently, two groups have reported the generation of a “knock-out” mouselacking the VR1 receptor. Electrophysiological studies of sensoryneurons (dorsal root ganglia) from these animals revealed a markedabsence of responses evoked by noxious stimuli including capsaicin,heat, and reduced pH. These animals did not display any overt signs ofbehavioral impairment and showed no differences in responses to acutenon-noxious thermal and mechanical stimulation relative to wild-typemice. The VR1 (−/−) mice also did not show reduced sensitivity to nerveinjury-induced mechanical or thermal nociception. However, the VR1knock-out mice were insensitive to the noxious effects of intradermalcapsaicin, exposure to intense heat (50-55° C.), and failed to developthermal hyperalgesia following the intradermal administration ofcarrageenan.

The compounds of the present invention are novel VR1 antagonists andhave utility in treating pain, bladder overactivity, and urinaryincontinence.

SUMMARY OF THE PRESENT INVENTION

The present invention discloses fused azabicyclic compounds, a methodfor inhibiting the VR1 receptor in mammals using these compounds, amethod for controlling pain in mammals, and pharmaceutical compositionsincluding those compounds. More particularly, the present invention isdirected to compounds of formula (I)

or a pharmaceutically acceptable salt or prodrug thereof, wherein

-   -   — is absent or a single bond;    -   X₁ is selected from the group consisting of N and CR₁;    -   X₂ is selected from the group consisting of N and CR₂;    -   X₃ is selected from the group consisting of N, NR₃, and CR₃;    -   X₄ is a bond or selected from the group consisting of N and CR₄;    -   X₅ is selected from the group consisting of N and C;    -   provided that when X₄ is a bond, one of X₁, X₂, or X₃ must be        NR₃;    -   Z₁ is selected from the group consisting of O, NH, and S;    -   Z₂ is a bond or selected from the group consisting of NH and O;    -   L is selected from the group consisting of alkenylene, alkylene,        alkynylene, cycloalkylene,

—(CH₂)_(m)O(CH₂)_(n)—, and N(R_(Y)), wherein the left end of—(CH₂)_(m)O(CH₂)_(n)— is attached to Z₂ and the right end is attached toR₉;

-   -   m and n are each independently 0-6;    -   R_(Y) is selected from the group consisting of hydrogen and        alkyl;    -   R₁, R₃, R₅, R₆, and R₇ are each independently selected from the        group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy,        alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,        alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio,        alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl,        cycloalkylalkyl, formyl, formylalkyl, haloalkoxy, haloalkyl,        haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto,        mercaptoalkyl, nitro, (CF₃)₂(HO)C—, —NR_(A)S(O)₂R_(B),        —S(O)₂OR_(A), —S(O)₂R_(B), —NZ_(A)Z_(B), (NZ_(A)Z_(B))alkyl,        (NZ_(A)Z_(B))carbonyl, (NZ_(A)Z_(B))carbonylalkyl and        (NZ_(A)Z_(B))sulfonyl, wherein Z_(A) and Z_(B) are each        independently selected from the group consisting of hydrogen,        alkyl, alkylcarbonyl, formyl, aryl, and arylalkyl;

R₂ and R₄ are each independently selected from the group consisting ofhydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl,alkylcarbonyloxy, alkylthio, alkynyl, carboxy, carboxyalkyl, cyano,cyanoalkyl, cycloalkyl, cycloalkylalkyl, formyl, formylalkyl,haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl,mercapto, mercaptoalkyl, nitro, (CF₃)₂(HO)C—, —NR_(A)S(O)₂R_(B),—S(O)₂OR_(A), —S(O)₂R_(B), —NZ_(A)Z_(B), (NZ_(A)Z_(B))alkyl,(NZ_(A)Z_(B))alkylcarbonyl, (NZ_(A)Z_(B))carbonyl,(NZ_(A)Z_(B))carbonylalkyl, (NZ_(A)Z_(B))sulfonyl, (NZ_(A)Z_(B))C(═NH)—,(NZ_(A)Z_(B))C(═NCN)NH—, and (NZ_(A)Z_(B))C(═NH)NH—;

-   -   R_(A) is selected from the group consisting of hydrogen and        alkyl;    -   R_(B) is selected from the group consisting of alkyl, aryl, and        arylalkyl;    -   R_(8a) is selected from the group consisting of hydrogen and        alkyl;    -   R_(8b) is absent when X₅ is N or R_(8b) is selected from the        group consisting of hydrogen, alkoxy, alkoxycarbonylalkyl,        alkyl, alkylcarbonyloxy, alkylsulfonyloxy, halogen, and hydroxy        when X₅ is C; and    -   R₉ is selected from the group consisting of hydrogen, aryl,        cycloalkyl, and heterocycle.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

In the principle embodiment, compounds of formula (I) are disclosed

or a pharmaceutically acceptable salt or prodrug thereof, wherein

-   -   — is absent or a single bond;    -   X₁ is selected from the group consisting of N and CR₁;    -   X₂ is selected from the group consisting of N and CR₂;    -   X₃ is selected from the group consisting of N, NR₃, and CR₃;    -   X₄ is a bond or selected from the group consisting of N and CR₄;    -   X₅ is selected from the group consisting of N and C;    -   provided that when X₄ is a bond, one of X₁, X₂, or X₃ must be        NR₃;    -   Z₁ is selected from the group consisting of O, NH, and S;    -   Z₂ is a bond or selected from the group consisting of NH and O;    -   L is selected from the group consisting of alkenylene, alkylene,        alkynylene, cycloalkylene,

—(CH₂)_(m)O(CH₂)_(n)—, and N(R_(Y)), wherein the left end of—(CH₂)_(m)O(CH₂)_(n)— is attached to Z₂ and the right end is attached toR₉;

-   -   m and n are each independently 0-6;    -   R_(Y) is selected from the group consisting of hydrogen and        alkyl;    -   R₁, R₃, R₅, R₆, and R₇ are each independently selected from the        group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy,        alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,        alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio,        alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl,        cycloalkylalkyl, formyl, formylalkyl, haloalkoxy, haloalkyl,        haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto,        mercaptoalkyl, nitro, (CF₃)₂(HO)C—, —NR_(A)S(O)₂R_(B),        —S(O)₂OR_(A), —S(O)₂R_(B), —NZ_(A)Z_(B), (NZ_(A)Z_(B))alkyl,        (NZ_(A)Z_(B))carbonyl, (NZ_(A)Z_(B))carbonylalkyl and        (NZ_(A)Z_(B))sulfonyl, wherein Z_(A) and Z_(B) are each        independently selected from the group consisting of hydrogen,        alkyl, alkylcarbonyl, formyl, aryl, and arylalkyl;

R₂ and R₄ are each independently selected from the group consisting ofhydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl,alkylcarbonyloxy, alkylthio, alkynyl, carboxy, carboxyalkyl, cyano,cyanoalkyl, cycloalkyl, cycloalkylalkyl, formyl, formylalkyl,haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl,mercapto, mercaptoalkyl, nitro, (CF₃)₂(HO)C—, —NR_(A)S(O)₂R_(B),—S(O)₂OR_(A), —S(O)₂R_(B), —NZ_(A)Z_(B), (NZ_(A)Z_(B))alkyl,(NZ_(A)Z_(B))alkylcarbonyl, (NZ_(A)Z_(B))carbonyl,(NZ_(A)Z_(B))carbonylalkyl, (NZ_(A)Z_(B))sulfonyl, (NZ_(A)Z_(B))C(═NH)—,(NZ_(A)Z_(B))C(═NCN)NH—, and (NZ_(A)Z_(B))C(═NH)NH—;

-   -   R_(A) is selected from the group consisting of hydrogen and        alkyl;    -   R_(B) is selected from the group consisting of alkyl, aryl, and        arylalkyl;    -   R_(8a) is selected from the group consisting of hydrogen and        alkyl;    -   R_(8b) is absent when X₅ is N or R_(8b) is selected from the        group consisting of hydrogen, alkoxy, alkoxycarbonylalkyl,        alkyl, alkylcarbonyloxy, alkylsulfonyloxy, halogen, and hydroxy        when X₅ is C; and    -   R₉ is selected from the group consisting of hydrogen, aryl,        cycloalkyl, and heterocycle.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; X₃ is N;X₄ is CR₄; and R₁, R₂, R₄, R₅, R₆, R₇, R_(8a), R_(8b), R₉, X₅, Z₁, Z₂,and L are as defined in formula (I).

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; X₃ is N;X₄ is CR₄; X₅ is N; R_(8b) is absent; Z₁, is O; Z₂ is NH; L is alkylene;R₉ is aryl; and R₁, R₂, R₄, R₅, R₆, R₇, and R_(8a) are as defined informula (I).

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; X₃ is N;X₄ is CR₄; X₅ is N; R₁, R₆ and R₇ are each hydrogen; R₂ and R₄ areindependently selected from the group consisting of hydrogen, alkyl,halogen, hydroxy, and —NZ_(A)Z_(B); R₅ is selected from the groupconsisting of hydrogen and halogen; R_(8a) is hydrogen; R_(8b) isabsent; Z₁ is O; Z₂ is NH; L is alkylene; R₉ is aryl wherein said arylis phenyl substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of hydrogen, alkoxy, alkyl,alkylsulfonyl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl,haloalkylthio, halogen, methylenedioxy, 4-morpholinyl,2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl,4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl,and —NZ_(C)Z_(D); and Z_(A), Z_(B), Z_(C), and Z_(D) are independentlyselected from the group consisting of hydrogen and alkyl.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; X₃ is N;X₄ is CR₄; X₅ is N; R₁, R₂, R₄, R₅, R₆ and R₇ are each hydrogen; R_(8b)is absent; Z₁ is O; Z₂ is NH; L is alkylene; R₉ is aryl wherein saidaryl is substituted with aryloxy; and R_(8a) is as defined in formula(I).

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; X₃ is N;X₄ is CR₄; X₅ is N; R₁, R₂, R₄, R₅, R₆, R₇, and R_(8a) are eachhydrogen; R_(8b) is absent; Z₁ is O; Z₂ is NH; L is alkylene; R₉ is arylwherein said aryl is phenyl substituted with aryloxy wherein saidaryloxy is phenoxy substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of hydrogen, alkoxy,alkyl, alkylsulfonyl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy,haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl,2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl,4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl,and —NZ_(C)Z_(D); and Z_(C) and Z_(D) are independently selected fromthe group consisting of hydrogen and alkyl.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; X₃ is N;X₄ is CR₄; X₅ is N; R₁, R₂, R₄, R₅, R₆, R₇, and R_(8a) are eachhydrogen; R_(8b) is absent; Z₁ is O; Z₂ is NH; L is alkylene; and R₉ isaryl wherein said aryl is napthyl.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; X₃ is N;X₄ is CR₄; X₅ is N; R_(8b) is absent; Z₁ is O; Z₂ is NH; L is alkylene;R₉ is cycloalkyl; R₁, R₂, R₄, R₅, R₆, R₇, and R_(8a) is as defined informula (I).

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; X₃ is N;X₄ is CR₄; X₅ is N; R₁, R₆ and R₇ are each hydrogen; R₂ and R₄ areindependently selected from the group consisting of hydrogen, alkyl,halogen, hydroxy, and —NZ_(A)Z_(B); R₅ is selected from the groupconsisting of hydrogen and halogen; R_(8a) is hydrogen; R_(8b) isabsent; Z₁ is O; Z₂ is NH; L is alkylene; R₉ is cycloalkyl wherein saidcyloalkyl is selected from the group consisting of adamantanyl,bicyclo[3.1.1]heptane, and cyclohexyl, wherein the cycloalkyl issubstituted with 1 or 2 substituents selected from the group consistingof hydrogen and alkyl; and Z_(A) and Z_(B) are independently selectedfrom the group consisting of hydrogen and alkyl.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; X₃ is N;X₄ is CR₄; X₅ is N; R_(8b) is absent; Z₁ is O; Z₂ is NH; L is alkylene;R₉ is heterocycle; and R₁, R₂, R₄, R₅, R₆, R₇, and R_(8a) are as definedin formula (I).

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; X₃ is N;X₄ is CR₄; X₅ is N; R₁, R₆ and R₇ are each hydrogen; R₂ and R₄ areindependently selected from the group consisting of hydrogen, alkyl,halogen, hydroxy, and —NZ_(A)Z_(B); R₅ is selected from the groupconsisting of hydrogen and halogen; R_(8a) is hydrogen; R_(8b) isabsent; Z₁ is O; Z₂ is NH; L is alkylene; R₉ is heterocycle wherein saidheterocycle is pyridinyl substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of hydrogen, alkoxy,alkyl, alkylsulfonyl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy,haloalkyl, haloalkylthio, halogen, 4-morpholinyl,2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl,4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl,and —NZ_(C)Z_(D); and Z_(A), Z_(B), Z_(C), and Z_(D) are independentlyselected from the group consisting of hydrogen and alkyl.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; X₃ is N;X₄ is CR₄; X₅ is N; Z₁ is O; Z₂ is NH; R_(8b) is absent; R₉ is hydrogen;and L, R₁, R₂, R₄, R₅, R₆, R₇, and R_(8a) are as defined in formula (I).

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; X₃ is N;X₄ is CR₄; X₅ is N; R₁, R₂, R₄, R₅, R₆, R₇, and R_(8a) are eachhydrogen; R_(8b) is absent; Z₁ is O; Z₂ is NH; L is alkylene; and R₉ ishydrogen.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; X₃ is N;X₄ is CR₄; X₅ is N; Z₁ is O; Z₂ is NH; L is cycloalkylene; R_(8b) isabsent; R₉ is aryl; and R₁, R₂, R₄, R₅, R₆, R₇, and R_(8a) are asdefined in formula (I).

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁ ; X₂ is CR₂; X₃ isN; X₄ is CR₄; X₅ is N; R₁, R₂, R₄, R₅, R₆, R₇, and R_(8a) are eachhydrogen; R_(8b) is absent; Z₁ is O; Z₂ is NH; L is cycloalkylene; R₉ isaryl wherein said aryl is phenyl substituted with 1, 2, or 3substituents independently selected from the group consisting ofhydrogen, alkoxy, alkyl, alkylsulfonyl, 1-azepanyl, 1-azocanyl, cyano,haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy,4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl,4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl,and —NZ_(C)Z_(D); and Z_(C) and Z_(D) are independently selected fromthe group consisting of hydrogen and alkyl.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; X₃ is N;X₄ is CR₄; X₅ is N; Z₁ is O; Z₂ is a bond; L is cycloalkylene; R_(8b) isabsent; R₉ is aryl; and R₁, R₂, R₄, R₅, R₆, R₇, and R_(8a) are asdefined in formula (I).

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; X₃ is N;X₄ is CR₄; X₅ is N; R₁, R₂, R₄, R₅, R₆, R₇, and R_(8a) are eachhydrogen; R_(8b) is absent; Z₁ is O; Z₂ is a bond; L is cycloalkylene;R₉ is aryl wherein said aryl is phenyl substituted with 1, 2, or 3substituents independently selected from the group consisting ofhydrogen, alkoxy, alkyl, alkylsulfonyl, 1-azepanyl, 1-azocanyl, cyano,haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy,4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl,4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl,and —NZ_(C)Z_(D); and Z_(C) and Z_(D) are independently selected fromthe group consisting of hydrogen and alkyl.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; X₃ is N;X₄ is CR₄; X₅ is N; Z₁ is O; Z₂ is NH; L is —(CH₂)_(m)O(CH₂)_(n)—wherein the left end is attached to Z₂ and the right end is attached toR₉; R_(8b) is absent; R₉ is aryl; and m, n, R₁, R₂, R₄, R₅, R₆, R₇, andR_(8a) are as defined in formula (I).

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; X₃ is N;X₄ is CR₄; X₅ is N; R₁, R₂, R₄, R₅, R₆, R₇, and R_(8a) are eachhydrogen; R_(8b) is absent; Z₁ is O; Z₂ is NH; L is—(CH₂)_(m)O(CH₂)_(n)— wherein the left end is attached to Z₂ and theright end is attached to R₉; m is 0-2; n is 0-2; R₉ is aryl wherein saidaryl is phenyl substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of hydrogen, alkoxy, alkyl,alkylsulfonyl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl,haloalkylthio, halogen, methylenedioxy, 4-morpholinyl,2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl,4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl,and —NZ_(C)Z_(D); and Z_(C) and Z_(D) are independently selected fromthe group consisting of hydrogen and alkyl.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; X₃ is N;X₄ is CR₄; X₅ is N; Z₁ is O; Z₂ is NH; L is N(R_(Y)); R_(8b) is absent;R₉ is aryl; and R_(Y), R₁, R₂, R₄, R₅, R₆, R₇, and R_(8a) are as definedin formula (I).

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; X₃ is N;X₄ is CR₄; X₅ is N; R_(Y), R₁, R₂, R₄, R₅, R₆, R₇, and R_(8a) are eachhydrogen; R_(8b) is absent; Z₁ is O; Z₂ is NH; L is N(R_(Y)); R₉ is arylwherein said aryl is phenyl substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of hydrogen, alkoxy,alkyl, alkylsulfonyl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy,haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl,2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl,4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl,and —NZ_(C)Z_(D); and Z_(C) and Z_(D) are independently selected fromthe group consisting of hydrogen and alkyl.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; X₃ is N;X₄ is CR₄; X₅ is N; Z₁ is O; Z₂ is a bond;

L is

R_(8b) is absent; R₉ is aryl; and R_(Y), R₁, R₂, R₄, R₅, R₆, R₇, andR_(8a) are as defined in formula (I).

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; X₃ is N;X₄ is CR₄; X₅ is N; R₁, R₅, R₆, R₇, and R_(8a) are each hydrogen; R_(8b)is absent; R₂ is selected from the group consisting of hydrogen andalkyl; Z₁ is O; Z₂ is a bond;

L is

R₉ is aryl wherein said aryl is phenyl substituted with 1, 2, or 3substituents independently selected from the group consisting ofhydrogen, alkoxy, alkyl, alkylsulfonyl, 1-azepanyl, 1-azocanyl, cyano,haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy,4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl,4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl,and —NZ_(C)Z_(D); and R_(Y), Z_(C), and Z_(D) are independently selectedfrom the group consisting of hydrogen and alkyl.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; X₃ is N;X₄ is CR₄; X₅ is N; R₁, R₂, R₄, R₅ and R₆ are each hydrogen; R₇ is(CF₃)₂(HO)C—; R_(8b) is absent; Z₁ is O; Z₂ is NH; L is alkylene; R₉ isaryl wherein said aryl is phenyl substituted with 1, 2, or 3substituents independently selected from the group consisting ofhydrogen, alkoxy, alkyl, alkylsulfonyl, 1-azepanyl, 1-azocanyl, cyano,haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy,4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl,4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl,and —NZ_(C)Z_(D); and R_(8a), Z_(C), and Z_(D) are independentlyselected from the group consisting of hydrogen and alkyl.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; X₃ is N;X₄ is CR₄; X₅ is N; Z₁ is O; Z₂ is O; L is alkylene; R_(8b) is absent;R₉ is aryl; R₁, R₂, R₄, R₅, R₆, R₇, and R_(8a) are as defined in formula(I).

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; X₃ is N;X₄ is CR₄; X₅ is N; R₁, R₂, R₄, R₅, R₆, R₇, and R_(8a) are eachhydrogen; R_(8b) is absent; Z₁ is O; Z₂ is O; L is alkylene; R₉ is arylwherein said aryl is phenyl substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of hydrogen, alkoxy,alkyl, alkylsulfonyl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy,haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl,2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl,4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl,and —NZ_(C)Z_(D); and Z_(C) and Z_(D) are independently selected fromthe group consisting of hydrogen and alkyl.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; X₃ is N;X₄ is CR₄; X₅ is N; R₁, R₂, R₄, R₅, R₆ and R₇ are each hydrogen; Z₁ isO; Z₂ is O; L is alkylene; R_(8b) is absent; R₉ is aryl wherein saidaryl is naphthyl; and R_(8a) is as defined in formula (I).

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; X₃ is N;X₄ is CR₄; X₅ is N; R_(8b) is absent; Z₁ is O; Z₂ is a bond; L isalkenylene; R₉ is aryl; and R₁, R₂, R₄, R₅, R₆, R₇, and R_(8a) are asdefined in formula (I).

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; X₃ is N;X₄ is CR₄; X₅ is N; R₁, R₆ and R₇ are each hydrogen; R₂ and R₄ areindependently selected from the group consisting of hydrogen, alkyl,halogen, hydroxy, and —NZ_(A)Z_(B); R₅ is selected from the groupconsisting of hydrogen and halogen; R_(8a) is hydrogen; R_(8b) isabsent; Z₁ is O; Z₂ is a bond; L is alkenylene; R₉ is aryl wherein saidaryl is phenyl substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of hydrogen, alkoxy, alkyl,alkylsulfonyl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl,haloalkylthio, halogen, methylenedioxy, 4-morpholinyl,2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl,4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl,and —NZ_(C)Z_(D); and Z_(A), Z_(B), Z_(C) and Z_(D) are independentlyselected from the group consisting of hydrogen and alkyl.

In another embodiment of the present invention, compounds offormula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; X₃ is N;X₄ is CR₄; X₅ is C; Z₁ is O; Z₂ is NH; L is alkylene; R₉ is heterocycle;and R₁, R₂, R₄, R₅, R₆, R₇, R_(8a), and R_(8b) are as defined in formula(I).

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; X₃ is N;X₄ is CR₄; X₅ is C; R₁, R₆ and R₇ are each hydrogen; R₂ and R₄ areindependently selected from the group consisting of hydrogen, alkyl,halogen, hydroxy, and —NZ_(A)Z_(B); R₅ is selected from the groupconsisting of hydrogen and halogen; R_(8a) and R_(8b) are hydrogen; Z₁is O; Z₂ is NH; L is alkylene; R₉ is heterocycle wherein saidheterocycle is selected from the group consisting of imidazolyl,pyridinyl, pyrrolidinyl, and thienyl, wherein the heterocycle issubstituted with 1 or 2 substituents independently selected from thegroup consisting of hydrogen, alkoxy, alkyl, alkylsulfonyl, 1-azepanyl,1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, oxo,4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl,4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl,and —NZ_(C)Z_(D); and Z_(A), Z_(B), Z_(C) and Z_(D) are independentlyselected from the group consisting of hydrogen and alkyl.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; X₃ is N;X₄ is CR₄; X₅ is C; Z₁ is O; Z₂ is NH; L is —(CH₂)_(m)O(CH₂)_(n)—wherein the left end is attached to Z₂ and the right end is attached toR₉; R₉ is hydrogen; and m, n, R₁, R₂, R₄, R₅, R₆, R₇, R_(8a), and R_(8b)are as defined in formula (I).

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; X₃ is N;X₄ is CR₄; X₅ is C; R₁, R₆ and R₇ are each hydrogen; R₂ and R₄ areindependently selected from the group consisting of hydrogen, alkyl,halogen, hydroxy, and —NZ_(A)Z_(B); R₅ is selected from the groupconsisting of hydrogen and halogen; R_(8a) and R_(8b) are hydrogen; Z₁is O; Z₂ is NH; L is —(CH₂)_(m)O(CH₂)_(n)— wherein the left end isattached to Z₂ and the right end is attached to R₉; m is 0-4; n is 0-4;R₉ is hydrogen; and Z_(A) and Z_(B) are independently selected from thegroup consisting of hydrogen and alkyl.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; X₃ is N;X₄ is CR₄; X₅ is C; Z₁ is O; Z₂ is NH; L is alkylene; R₉ is aryl; andR₁, R₂, R₄, R₅, R₆, R₇, R_(8a), and R_(8b) are as defined in formula(1).

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; X₃ is N;X₄ is CR₄; X₅ is C; R₁, R₆, R₇, R_(8a) and R_(8b) are each hydrogen; R₂and R₄ are independently selected from the group consisting of hydrogen,alkyl, halogen, hydroxy, and —NZ_(A)Z_(B); R₅ is selected from the groupconsisting of hydrogen and halogen; Z₁ is O; Z₂ is NH; L is alkylene; R₉is aryl wherein said aryl is phenyl substituted with 1, 2, or 3substituents independently selected from the group consisting ofhydrogen, alkoxy, alkyl, alkylsulfonyl, 1-azepanyl, 1-azocanyl, cyano,haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy,4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl,4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl,and —NZ_(C)Z_(D); and Z_(A), Z_(B), Z_(C) and Z_(D) are independentlyselected from the group consisting group consisting of hydrogen andalkyl.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; X₃ is N;X₄ is CR₄; X₅ is C; R₁, R₆, and R₇ are each hydrogen; R₂ and R₄ areindependently selected from the group consisting of hydrogen, alkyl,halogen, hydroxy, and —NZ_(A)Z_(B); R₅ is selected from the groupconsisting of hydrogen and halogen; R_(8a) is selected from the groupconsisting of hydrogen and alkyl; R_(8b) is alkyl; Z₁ is O; Z₂ is NH; Lis alkylene; R₉ is aryl wherein said aryl is phenyl substituted with 1,2, or 3 substituents independently selected from the group consisting ofhydrogen, alkoxy, alkyl, alkylsulfonyl, 1-azepanyl, 1-azocanyl, cyano,haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy,4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl,4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl,and —NZ_(C)Z_(D); and Z_(A), Z_(B), Z_(C) and Z_(D) are independentlyselected from the group consisting of hydrogen and alkyl.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; X₃ is N;X₄ is CR₄; X₅ is C; R₁, R₆, and R₇ and are each hydrogen; R₂ and R₄ areindependently selected from the group consisting of hydrogen, alkyl,halogen, hydroxy, and —NZ_(A)Z_(B); R₅ is selected from the groupconsisting of hydrogen and halogen; R_(8a) is hydrogen; R_(8b) isselected from the group consisting of alkoxy, alkoxycarbonylalkyl,alkylcarbonyloxy, alkylsulfonyl, halogen, and hydroxy; Z₁ is O; Z₂ isNH; L is alkylene; R₉ is aryl wherein said aryl is phenyl substitutedwith 1, 2, or 3 substituents independently selected from the groupconsisting of hydrogen, alkoxy, alkyl, alkylsulfonyl, 1-azepanyl,1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen,methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl,1-piperidinyl, 4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl,4-thiomorpholinyl, and —NZ_(C)Z_(D); and Z_(A), Z_(B), Z_(C) and Z_(D)are independently selected from the group consisting of hydrogen andalkyl.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; X₃ is N;X₄ is CR₄; X₅ is C; R₁, R₆, R₇, and R₇ are each hydrogen; R₂ and R₄ areindependently selected from the group consisting of hydrogen, alkyl,halogen, hydroxy, and —NZ_(A)Z_(B); R₅ is selected from the groupconsisting of hydrogen and halogen; R_(8a) is selected from the groupconsisting of hydrogen and alkyl; R_(8b) is selected from the groupconsisting of hydrogen, alkoxycarbonylalkyl, alkyl, and hydroxy; Z₁ isO; Z₂ is O; L is alkylene; R₉ is hydrogen; and Z_(A) and Z_(B) areindependently selected from the group consisting of hydrogen and alkyl.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; X₃ is N;X₄ is N; and R₁, R₂, R₅, R₆, R₇, R_(8a), R_(8b), R₉, X₅, Z₁, Z₂, and Lare as defined in formula (I).

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; X₃ is N;X₄ is N; X₅ is N; R_(8b) is absent; Z₁ is O; Z₂ is NH; L is alkylene; R₉is aryl; and R₁, R₂, R₅, R₆, R₇, R_(8a), and R_(8b) are as defined informula (I).

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; X₃ is N;X₄ is N; X₅ is N; R₁, R₅, R₆ and R₇ are each hydrogen; R_(8b) is absent;R₂ is selected from the group consisting of alkyl and halogen; Z₁ is O;Z₂ is NH; L is alkylene; R₉ is aryl wherein said aryl is phenylsubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of hydrogen, alkoxy, alkyl, alkylsulfonyl, 1-azepanyl,1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen,methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl,1-piperidinyl, 4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl,4-thiomorpholinyl, and —NZ_(C)Z_(D); and R_(8a), Z_(C), and Z_(D) areindependently selected from the group consisting of hydrogen and alkyl.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is N; X₃ is CR₃;X₄ is CR₄; and R₁, R₃, R₅, R₆, R₇, R_(8a), R_(8b), R₉, X₅, Z₁, Z₂, and Lare as defined in formula (I).

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is N; X₃ is CR₃;X₄ is CR₄; X₅ is N; R_(8b) is absent; Z₁ is O; Z₂ is NH; L is alkylene;R₉ is aryl; and R₁, R₃, R₅, R₆, R₇, and R_(8a) are as defined in formula(I).

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is a single bond; X₁ is CR₁; X₂ is N; X₃ is CR₃;X₄ is CR₄; X₅ is N; R₁, R₃, R₄, R₅, R₆ and R₇ are each hydrogen; R_(8b)is absent; Z₁ is O; Z₂ is NH; L is alkylene; R₉ is aryl wherein saidaryl is phenyl substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of hydrogen, alkoxy, alkyl,alkylsulfonyl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl,haloalkylthio, halogen, methylenedioxy, 4-morpholinyl,2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl,4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl,and —NZ_(C)Z_(D); and R_(8a), Z_(C), and Z_(D) are independentlyselected from the group consisting of hydrogen and alkyl.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is absent; X₁ is CR₁; X₂ is CR₂; X₃ is N; X₄ isa bond; and R₁, R₂, R₅, R₆, R₇, R_(8a), R_(8b), R₉, X₅, Z₁, Z₂, and Lare as defined in formula (I).

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is absent; X₁ is CR₁; X₂ is CR₂; X₃ is N; X₄ isa bond; X₅ is N; R_(8b) is absent; Z₁ is O; Z₂ is NH; L is alkylene; R₉is aryl; and R₁, R₂, R₅, R₆, R₇, and R_(8a) are as defined in formula(I).

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is absent; X₁ is CR₁; X₂ is CR₂; X₃ is N; X₄ isa bond; X₅ is N; R₁, R₂, R₅, R₆ and R₇ are each hydrogen; R_(8b) isabsent; Z₁ is O; Z₂ is NH; L is alkylene; R₉ is aryl wherein said arylis phenyl substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of hydrogen, alkoxy, alkyl,alkylsulfonyl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl,haloalkylthio, halogen, methylenedioxy, 4-morpholinyl,2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl,4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl,and —NZ_(C)Z_(D); and R_(8a), Z_(C), and Z_(D) are independentlyselected from the group consisting of hydrogen and alkyl.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is absent; X₁ is CR₁; X₂ is CR₂; X₃ is N; X₄ isa bond; X₅ is N; R₁ and R₂ are each independently alkyl; R₅, R₆ and R₇are each hydrogen; R_(8b) is absent; Z₁ is O; Z₂ is NH; L is alkylene;R₉ is aryl wherein said aryl is phenyl substituted with 1, 2, or 3substituents independently selected from the group consisting ofhydrogen, alkoxy, alkyl, alkylsulfonyl, 1-azepanyl, 1-azocanyl, cyano,haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy,4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl,4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl,and —NZ_(C)Z_(D); and R_(8a), Z_(C), and Z_(D) are independentlyselected from the group consisting of hydrogen and alkyl.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is absent; X₁ is CR₁; X₂ is CR₂; X₃ is N; X₄ isa bond; X₅ is N; R_(8b) is absent; Z₁ is O; Z₂ is O; L is alkylene; R₉is aryl; and R₁, R₂, R₅, R₆, R₇, R_(8a), and R₉ are as defined informula (I).

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is absent; X₁ is CR₁; X₂ is CR₂; X₃ is N; X₄ isa bond; X₅ is N; R₁, R₂, R₅, R₆ and R₇ are each hydrogen; R_(8b) isabsent; Z₁ is O; Z₂ is O; L is alkylene; R₉ is aryl wherein said aryl isphenyl substituted with 1, 2, or 3 substituents independently selectedfrom the group consisting of hydrogen, alkoxy, alkyl, alkylsulfonyl,1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio,halogen, methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl,phenyl, 1-piperidinyl, 4-methyl-1-piperidinyl, pyridinyl,1-pyrrolidinyl, 4-thiomorpholinyl, and —NZ_(C)Z_(D); and R_(8a), Z_(C),and Z_(D) are independently selected from the group consisting ofhydrogen and alkyl.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is absent; X₁ is CR₁; X₂ is N; X₃ is NR₃; X₄ isa bond; and R₁, R₃, R₅, R₆, R₇, R_(8a), R_(8b), R₉, X₅, Z₁, Z₂, and Lare as defined in formula (I).

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is absent; X₁ is CR₁; X₂ is N; X₃ is NR₃; X₄ isa bond; X₅ is N; R_(8b) is absent; Z₁ is O; Z₂ is NH; L is alkylene; R₉is aryl; and R₁, R₃, R₅, R₆, R₇, and R_(8a) are as defined in formula(I).

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein — is absent; X₁ is CR₁; X₂ is N; X₃ is NR₃; X₄ isa bond; X₅ is N; R₁, R₅, R₆ and R₇ are each hydrogen; R_(8b) is absent;Z₁ is O; Z₂ is NH; L is alkylene; R₉ is aryl wherein said aryl is phenylsubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of hydrogen, alkoxy, alkyl, alkylsulfonyl, 1-azepanyl,1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen,methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl,1-piperidinyl, 4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl,4-thiomorpholinyl, and —NZ_(C)Z_(D); and R_(8a), Z_(C), and Z_(D) areindependently selected from the group consisting of hydrogen and alkyl.

Another embodiment of the present invention relates to pharmaceuticalcompositions comprising a therapeutically effective amount of a compoundof formula (I) or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention relates to a method oftreating a disorder wherein the disorder is ameliorated by inhibitingvanilloid receptor subtype 1 (VR1) receptor in a host mammal in need ofsuch treatment comprising administering a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof.

Another embodiment of the present invention relates to a method forcontrolling pain in a host mammal in need of such treatment comprisingadministering a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention relates to a method oftreating urinary incontinence in a host mammal in need of such treatmentcomprising administering a therapeutically effective amount of acompound of formula (I) or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention relates to a method oftreating bladder overactivity in a host mammal in need of such treatmentcomprising administering a therapeutically effective amount of acompound of formula (I) or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention relates to a method oftreating inflammatory thermal hyperalgesia in a host mammal in need ofsuch treatment comprising administering a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof.

Definition of Terms

As used throughout this specification and the appended claims, thefollowing terms have the following meanings:

The term “alkenyl” as used herein, means a straight orbranched chainhydrocarbon containing from 2 to 10 carbons and containing at least onecarbon-carbon double bond formed by the removal of two hydrogens.Representative examples of alkenyl include, but are not limited to,ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4pentenyl,5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term “alkenylene” means a divalent group derived from a straight orbranched chain hydrocarbon of from 2 to 10 carbon atoms containing atleast one double bond. Representative examples of alkenylene include,but are not limited to, —CH═CH—, —CH═CH₂CH₂—, and —CH═C(CH₃)CH₂—.

The term “alkoxy” as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, andhexyloxy.

The term “alkoxyalkoxy” as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through analkoxy group, as defined herein. Representative examples of alkoxyalkoxyinclude, but are not limited to, methoxymethoxy, ethoxymethoxy and2-ethoxyethoxy.

The term “alkoxyalkyl” as used herein, means an alkoxy group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of alkoxyalkyl include, butare not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl,and methoxymethyl.

The term “alkoxycarbonyl” as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkoxycarbonyl include, but are not limited to, methoxycarbonyl,ethoxycarbonyl, and tert-butoxycarbonyl.

The term “alkoxycarbonylalkyl” as used herein, means an alkoxycarbonylgroup, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofalkoxycarbonylalkyl include, but are not limited to,3-methoxycarbonylpropyl, 4-ethoxycarbonylbutyl, and2-tert-butoxycarbonylethyl.

The term “alkyl” as used herein, means a straight or branched chainhydrocarbon containing from 1 to 10 carbon atoms. Representativeexamples of alkyl include, but are not limited to, methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, andn-decyl.

The term “alkylcarbonyl” as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl,2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.

The term “alkylcarbonylalkyl” as used herein, means an alkylcarbonylgroup, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofalkylcarbonylalkyl include, but are not limited to, 2-oxopropyl,3,3-dimethyl-2-oxopropyl, 3-oxobutyl, and 3-oxopentyl.

The term “alkylcarbonyloxy” as used herein, means an alkylcarbonylgroup, as defined herein, appended to the parent molecular moietythrough an oxygen atom. Representative examples of alkylcarbonyloxyinclude, but are not limited to, acetyloxy, ethylcarbonyloxy, andtert-butylcarbonyloxy.

The term “alkylene” means a divalent group derived from a straight orbranched chain hydrocarbon of from 1 to 10 carbon atoms. Representativeexamples of alkylene include, but are not limited to, —CH₂—, —CH₂CH₂—,—CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, —CH₂CH(CH₃)CH₂—, and—(CH2)_(p)CH(R_(z))(CH₂)_(q)—, wherein p and q are independently 0-4 andR_(Z) is selected from the group consisting of aryl, cycloalkyl, andhydroxy. A preferred aryl group is phenyl.

The term “alkylsulfonyl” as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through asulfonyl group, as defined herein. Representative examples ofalkylsulfonyl include, but are not limited to, methylsulfonyl andethylsulfonyl.

The term “alkylthio” as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through a sulfur atom.Representative examples of alkylthio include, but are not limited,methylsulfanyl, ethylsulfanyl, tert-butylsulfanyl, and hexylsulfanyl.

The term “alkynyl” as used herein, means a straight or branched chainhydrocarbon group containing from 2 to 10 carbon atoms and containing atleast one carbon-carbon triple bond. Representative examples of alkynylinclude, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl,3-butynyl, 2-pentynyl, and 1-butynyl.

The term “alkynylene” means a divalent group derived from a straight orbranched chain hydrocarbon of from 2 to 10 carbon atoms containing atleast one triple bond. Representative examples of alkynylene include,but are not limited to, —C≡C—, —CH₂C≡C—, —CH(CH₃)CH₂C≡C—, —C≡CCH₂—, and—C≡—CCH(CH₃)CH₂—.

The term “aryl” as used herein, means a phenyl group, or a bicyclic or atricyclic fused ring system wherein one or more of the fused rings is aphenyl group. Bicyclic fused ring systems are exemplified by a phenylgroup fused to a cycloalkyl group, as defined herein, or another phenylgroup. Tricyclic fused ring systems are exemplified by a bicyclic fusedring system fused to a cycloalkyl group, as defined herein, or anotherphenyl group. Representative examples of aryl include, but are notlimited to, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl,naphthyl, phenyl and tetrahydronaphthyl.

The aryl groups of this invention can be substituted with 1, 2, 3, 4 or5 substituents independently selected from alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl,alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl,cycloalkyl, cycloalkylalkyl, ethylenedioxy, formyl, formylalkyl,haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl,methylenedioxy, mercapto, mercaptoalkyl, nitro, —NZ_(C)Z_(D),(NZ_(C)Z_(D))alkyl, (NZ_(C)Z_(D))carbonyl, (NZ_(C)Z_(D))carbonylalkyl,(NZ_(C)Z_(D))sulfonyl, —NR_(A)S(O)₂R_(B), —S(O)₂OR_(A) and —S(O)₂R_(A)wherein R_(A) and R_(B) are as defined herein. The aryl groups of thisinvention can be further substituted with any one of an additional aryl,arylalkyl, aryloxy, arylthio, heterocycle, heterocyclealkyl,heterocycleoxy, or heterocyclethio group, as defined herein, wherein theadditional aryl, arylalkyl, aryloxy, arylthio, heterocycle,heterocyclealkyl, heterocycleoxy, and heterocyclethio group can besubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl,alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkynyl, carboxy,carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formyl,formylalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy,hydroxyalkyl, mercapto, mercaptoalkyl, nitro, —NZ_(C)Z_(D),(NZ_(C)Z_(D))alkyl, (NZ_(C)Z_(D))carbonyl, (NZ_(C)Z_(D))carbonylalkyl,(NZ_(C)Z_(D))sulfonyl, —NR_(A)S(O)₂R_(B), —S(O)₂OR_(A) and —S(O)₂R_(A)wherein R_(A) and R_(B) are as defined herein. Representative examplesinclude, but are not limited to, 4-bromophenyl, 3-chlorophenyl,4-chlorophenyl, 3,4-dichlorophenyl, 2,3-dichlorophenyl,2,4-dichlorophenyl, 3,5-dichlorophenyl, 3,4-difluorophenyl,4-bromo-2-fluorophenyl, 4-chloro-2-fluorophenyl, 4-(tert-butyl)phenyl),4-cyanophenyl, 4-ethylphenyl, 3-fluorophenyl, 2,4-difluorophenyl,4-bromo-3-fluorophenyl, 2,3-difluoro-4-(trifluoromethyl)phenyl,3-fluoro-4-(trifluoromethyl)phenyl, 3-fluoro-5-(trifluoromethyl)phenyl,3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl,4-(trifluoromethoxy)phenyl, 3-(trifluoromethoxy)phenyl,4-[(trifluoromethyl)thio]phenyl, 3-methylphenyl, 3,4-dimethylphenyl,2,4-dimethylphenyl, 4-isopropylphenyl, 4-methylphenyl,4-bromo-3-methylphenyl, 4-fluoro-3-(trifluoromethyl)phenyl,3-chloro-4-fluorophenyl, 4-(1-pyrrolidinyl)phenyl, 4-(1-azepanyl)phenyl,3-fluoro-4-(1-pyrrolidinyl)phenyl, 3-fluoro-4-(1-azepanyl)phenyl,4-(1-azocanyl)phenyl, 4-(1-piperidinyl)phenyl,3-fluoro-4-(1-piperidinyl)phenyl, 4-(2-pyridinyl)phenyl, 1,1′-biphenyl,3-fluoro-4-(4-methyl-1-piperidinyl)phenyl,4-(4-methyl-1-piperidinyl)phenyl, 4-(4-morpholinyl)phenyl,4-(2,6-dimethyl-4-morpholinyl)phenyl, 4-(4-thiomorpholinyl)phenyl,3,5-difluoro-4-(4-morpholinyl)phenyl, 3,5-bis(trifluoromethyl)phenyl,and 2,5-bis(trifluoromethyl)phenyl.

The term “arylalkyl” as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of arylalkyl include, but arenot limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and2-naphth-2-ylethyl.

The term “aryloxy” as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of aryloxy include, but are not limited to,phenoxy, naphthyloxy, 3-bromophenoxy, 4-chlorophenoxy, 4-methylphenoxy,and 3,5-dimethoxyphenoxy.

The term “arylthio” as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through a sulfur atom.Representative examples of arylthio include, but are not limited to,phenylsulfanyl, naphth-2-ylsulfanyl, and 5-phenylhexylsulfanyl.

The term “carbonyl” as used herein, means a —C(O)— group.

The term “1-azepanyl” as used herein, means a 7-membered ring whereinone of the atoms is nitrogen.

The term “1-azocanyl” as used herein, means a 8-membered ring whereinone of the atoms is nitrogen.

The term “carboxy” as used herein, means a —CO₂H group.

The term “carboxyalkyl” as used herein, means a carboxy group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of carboxyalkylinclude, but are not limited to, carboxymethyl, 2-carboxyethyl, and3-carboxypropyl.

The term “cyano” as used herein, means a —CN group.

The term “cyanoalkyl” as used herein, means a cyano group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of cyanoalkyl include, butare not limited to, cyanomethyl, 2-cyanoyethyl, and 3-cyanopropyl.

The term “cycloalkyl” as used herein, means a monocyclic, bicyclic, ortricyclic ring system. Monocyclic ring systems are exemplified by asaturated cycic hydrocarbon group containing from 3 to 8 carbon atoms.Examples of monocyclic ring systems include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Bicyclic ringsystems are exemplified by a bridged monocyclic ring system in which twonon-adjacent carbon atoms of the monocyclic ring are linked by analkylene bridge of between one and three additional carbon atoms.Representative examples of bicyclic ring systems include, but are notlimited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane,bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, andbicyclo[4.2.1]nonane. Tricyclic ring systems are exemplified by abicyclic ring system in which two nonadjacent carbon atoms of thebicyclic ring are linked by a bond or an alkylene bridge of between oneand three carbon atoms. Representative examples of tricyclic-ringsystems include, but are not limited to, tricyclo[3.3.1.0^(3,7)]nonaneand tricyclo[3.3.1.1^(3,7)]decane (adamantyl).

The cycloalkyl groups of this invention can be substituted with 1, 2, 3,4 or 5 substituents independently selected from alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl,alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl,haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl,mercapto, mercaptoalkyl, nitro, —NZ_(C)Z_(D), (NZ_(C)Z_(D))alkyl,(NZ_(C)Z_(D))carbonyl, (NZ_(C)Z_(D))carbonylalkyl,(NZ_(C)Z_(D))sulfonyl, —NR_(A)S(O)₂R_(B), —S(O)₂OR_(A), and —S(O)₂R_(A)wherein R_(A) and R_(B) are as defined herein. Representative examplesinclude, but are not limited to, 6,6-dimethylbicyclo[3.1.1]heptyl,6,6-dimethylbicyclo[3.1.1]hept-2-yl, 4-tert-butylcyclohexyl, and4-(trifluoromethyl)cyclohexyl.

The term “cycloalkylalkyl” as used herein, means a cycloalkyl group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of cycloalkylalkylinclude, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl,cyclopentylmethyl, cyclohexylmethyl, and 4-cycloheptylbutyl.

The term “cycloalkylene” as used herein, means a divalent group derivedfrom a cycloalkyl group, as defined herein. Representative examples ofcycloalkylene include, but are not limited to

The term “ethylenedioxy” as used herein, means a —(CH₂)₂O— group whereinthe oxygen atoms of the ethylenedioxy group are attached to the parentmolecular moiety through one carbon atom forming a 5 membered ring orthe oxygen atoms of the ethylenedioxy group are attached to the parentmolecular moiety through two adjacent carbon atoms forming a sixmembered ring.

The term “formyl” as used herein, means a —C(O)H group.

The term “formylalkyl” as used herein, means a formyl group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of formylalkyl include, butare not limited to, formylmethyl and 2-formylethyl.

The term “halo” or “halogen” as used herein, means —Cl, —Br, —I or —F.

The term “haloalkoxy” as used herein, means at least one halogen, asdefined herein, appended to the parent molecular moiety through analkoxy group, as defined herein. Representative examples of haloalkoxyinclude, but are not limited to, chloromethoxy, 2-fluoroethoxy,trifluoromethoxy, 2-chloro-3-fluoropentyloxy, and pentafluoroethoxy.

The term “haloalkyl” as used herein, means at least one halogen, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of haloalkyl include,but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl,pentafluoroethyl, and 2-chloro-3-fluoropentyl.

The term “haloalkylthio” as used herein, means at least one halogen, asdefined herein, appended to the parent molecular moiety through analkylthio group, as defined herein. Representative examples ofhaloalkylthio include, but are not limited to, trifluoromethylthio.

The term “heterocycle” or “heterocyclic” as used herein, means amonocyclic, bicyclic, or tricyclic ring system. Monocyclic ring systemsare exemplified by any 3 or 4-membered ring containing a heteroatomindependently selected from oxygen, nitrogen and sulfur; or a 5-, 6- or7-membered ring containing one, two or three heteroatoms wherein theheteroatoms are independently selected from nitrogen, oxygen and sulfur.The 5-membered ring has from 0-2 double bonds and the 6- and 7-memberedring have from 0-3 double bonds. Representative examples of monocyclicring systems include, but are not limited to, azetidinyl, azepanyl,aziridinyl, diazepinyl, 1,3-dioxolanyl, dioxanyl, dithianyl, furyl,imidazolyl, imidazolinyl, imidazolidinyl, isothiazolyl, isothiazolinyl,isothiazolidinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, morpholinyl,oxadiazolyl, oxadiazolinyl, oxadiazolidinyl, oxazolyl, oxazolinyl,oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl,pyrazolinyl, pyrazolidinyl, pyridinyl, pyrimidinyl,pyridazinyl,pyrrolyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl,tetrahydrothienyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiadiazolinyl,thiadiazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, thienyl,thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone),thiopyranyl, triazinyl, triazolyl, and trithianyl. Bicyclic ring systemsare exemplified by any of the above monocyclic ring systems fused to anaryl group as defined herein, a cycloalkyl group as defined herein, oranother monocyclic ring system. Representative examples of bicyclic ringsystems include but are not limited to, for example, benzimidazolyl,benzodioxinyl, benzothiazolyl, benzothienyl, benzotriazolyl,benzoxazolyl, benzofuranyl, benzopyranyl, benzothiopyranyl, cinnolinyl,indazolyl, indolyl, 2,3-dihydroindolyl, indolizinyl, naphthyridinyl,isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl,phthalazinyl, pyranopyridinyl, quinolinyl, quinolizinyl, quinoxalinyl,quinazolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, andthiopyranopyridinyl. Tricyclic rings systems are exemplified by any ofthe above bicyclic ring systems fused to an aryl group as definedherein, a cycloalkyl group as defined herein, or a monocyclic ringsystem. Representative examples of tricyclic ring systems include, butare not limited to, acridinyl, carbazolyl, carbolinyl,dibenzo[b,d]furanyl, dibenzo[b,d]thienyl, naphtho[2,3-b]furan,naphtho[2,3-b]thienyl, phenazinyl, phenothiazinyl, phenoxazinyl,thianthrenyl, thioxanthenyl and xanthenyl.

The heterocycles of this invention can be substituted with 1, 2, or 3substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy,alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl,alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkynyl,arylalkyl, aryloxy, arylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl,cycloalkyl, cycloalkylalkyl, formyl, formylalkyl, haloalkoxy, haloalkyl,haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl,nitro, oxo, —NZ_(C)Z_(D), (NZ_(C)Z_(D))alkyl, (NZ_(C)Z_(D))carbonyl,(NZ_(C)Z_(D))carbonylalkyl, (NZ_(C)Z_(D))sulfonyl, —NR_(A)S(O)₂R_(B),—S(O)₂OR_(A) and —S(O)₂R_(A) wherein R_(A) and R_(B) are as definedherein. The heterocycles of this invention can be further substitutedwith any one of an additional aryl, arylakyl, aryloxy, arylthio,heterocycle, heterocyclealkyl, heterocycleoxy, or heterocyclethio group,as defined herein, wherein the additional aryl, arylalkyl, aryloxy,arylthio, heterocycle, heterocyclealkyl, heterocycleoxy, andheterocyclethio group can be substituted with 1, 2, or 3 substituentsindependently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl,alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkynyl,carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl,ethylenedioxy, formyl, formylalkyl, haloalkoxy, haloalkyl,haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl,nitro, —NZ_(C)Z_(D), (NZ_(C)Z_(D))alkyl, (NZ_(C)Z_(D))carbonyl,(NZ_(C)Z_(D))carbonylalkyl, (NZ_(C)Z_(D))sulfonyl, —NR_(A)S(O)₂R_(B),—S(O)₂O R_(A) and —S(O)₂R_(A) wherein R_(A) and R_(B) are as definedherein. Representative examples include, but are not limited to,2,6-dimethylmorpholinyl, 4-(3-chlorophenyl)-1-piperazinyl,4-(3,4-dimethylphenyl)-1-piperazinyl, 4-(4-chlorophenyl)-1-piperazinyl,4-(4-methylphenyl)-3-methyl-1-piperazinyl,4-(2,3-dimethylphenyl)-1-piperazinyl,4-(2,3-dichlorophenyl)-1-piperazinyl,4-(3,4-dichlorophenyl)-1-piperazinyl,4-[3-(trifluoromethyl)phenyl]-1-piperazinyl,4-(4-bromophenyl)-1-piperazinyl, 2-oxo-1-pyrrolidinyl, and5-(trifluoromethyl)-2-pyridinyl.

The term “heterocyclealkyl” as used herein, means a heterocycle, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of heterocyclealkylinclude, but are not limited to, pyridin-3-ylmethyl and2-pyrimidin-2-ylpropyl.

The term “heterocycleoxy” as used herein, means a heterocycle group, asdefined herein, appended to the parent molecular moiety through anoxygen atom. Representative examples of heterocycleoxy include, but arenot limited to, pyridin-3-yloxy and quinolin-3-yloxy.

The term “heterocyclethio” as used herein, means a heterocycle group, asdefined herein, appended to the parent molecular moiety through a sulfuratom. Representative examples of heterocyclethio include, but are notlimited to, pyridin-3-ylsulfanyl and quinolin-3-ylsulfanyl.

The term “hydroxy” as used herein, means an —OH group.

The term “hydroxyalkyl” as used herein, means at least one hydroxygroup, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofhydroxyalkyl include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and2-ethyl-4-hydroxyheptyl.

The term “mercapto” as used herein, means a —SH group.

The term “mercaptoalkyl” as used herein, means a mercapto group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of mercaptoalkylinclude, but are not limited to, 2-mercaptoethyl and 3-mercaptopropyl.

The term “methylenedioxy” as used herein, means a —OCH₂O— group whereinthe oxygen atoms of the methylenedioxy are attached to the parentmolecular moiety through two adjacent carbon atoms.

The term “nitro” as used herein, means a —NO₂ group.

The term “—NZ_(A)Z_(B)” as used herein, means two groups, Z_(A) andZ_(B), which are appended to the parent molecular moiety through anitrogen atom. Z_(A) and Z_(B) are each independently selected fromhydrogen, alkyl, alkylcarbonyl, formyl, aryl and arylalkyl.Representative examples of —NZ_(A)Z_(B) include, but are not limited to,amino, methylamino, acetylamino, benzylamino, phenylamino, andacetylmethylamino.

The term “(NZ_(A)Z_(B))alkyl” as used herein, means a NZ_(A)Z_(B) group,as defined herein, appended to the parent molecular moiety through analkyl group, as defined herein. Representative examples of(NZ_(A)Z_(B))alkyl include, but are not limited to, aminomethyl,2-(methylamino)ethyl, 2-(dimethylamino)ethyl and(ethylmethylamino)methyl.

The term “(NZ_(A)Z_(B))alkylcarbonyl” as used herein, means a(NZ_(A)Z_(B))alkyl group, as defined herein, appended to the parentmolecular moiety through a carbonyl group, as defined herein.Representative examples of (NZ_(A)Z_(B))alkylcarbonyl include, but arenot limited to, dimethylaminomethylcarbonyl,2-(dimethylamino)ethylcarbonyl, and (ethylmethylamino)methylcarbonyl.

The term “(NZ_(A)Z_(B))carbonyl” as used herein, means a —NZ_(A)Z_(B)group, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein. Representative examples of(NZ_(A)Z_(B))carbonyl include, but are not limited to, aminocarbonyl,(methylamino)carbonyl, (dimethylamino)carbonyl and(ethylmethylamino)carbonyl.

The term “(NZ_(A)Z_(B))carbonylalkyl ” as used herein, means a(NZ_(A)Z_(B))carbonyl group, as defined herein, appended to the parentmolecular moiety through an alkyl group, as defined herein.Representative examples of (NZ_(A)Z_(B))carbonylalkyl include, but arenot limited to, (aminocarbonyl)methyl, 2-((methylamino)carbonyl)ethyland ((dimethylamino)carbonyl)methyl.

The term “(NZ_(A)Z_(B))sulfonyl” as used herein, means a —NZ_(A)Z_(B)group, as defined herein, appended to the parent molecular moietythrough a sulfonyl group, as defined herein. Representative examples of(NZ_(A)Z_(B))sulfonyl include, but are not limited to, aminosulfonyl,(methylamino)sulfonyl, (dimethylamino)sulfonyl and(ethylmethylamino)sulfonyl. The term “—NZ_(A)Z_(B)” as used herein,means two groups, Z_(A) and Z_(B), which are appended to the parentmolecular moiety through a nitrogen atom. Z_(A) and Z_(B) are eachindependently selected from hydrogen, alkyl, alkylcarbonyl, formyl, aryland arylalkyl. Representative examples of —NZ_(A)Z_(B) include, but arenot limited to, amino, methylamino, acetylamino, benzylamino,phenylamino, and acetylmethylamino.

The term “—NZ_(C)Z_(D)” as used herein, means two groups, Z_(C) andZ_(D), which are appended to the parent molecular moiety through anitrogen atom. Z_(C) and Z_(D) are each independently selected fromhydrogen, alkyl, alkylcarbonyl, formyl, aryl and arylalkyl.Representative examples of —NZ_(C)Z_(D) include, but are not limited to,amino, methylamino, acetylamino, benzylamino, phenylamino, andacetylmethylamino.

The term “(NZ_(C)Z_(D))alkyl” as used herein, means a NZ_(C)Z_(D) group,as defined herein, appended to the parent molecular moiety through analkyl group, as defined herein. Representative examples of(NZ_(C)Z_(D))alkyl include, but are not limited to, aminomethyl,2-methylamino)ethyl, 2-(dimethylamino)ethyl and(ethylmethylamino)methyl.

The term “(NZ_(C)Z_(D))carbonyl ” as used herein, means a —NZ_(C)Z_(D)group, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein. Representative examples of(NZ_(C)Z_(D))carbonyl include, but are not limited to, aminocarbonyl,(methylamino)carbonyl, (dimethylamino)carbonyl and(ethylmethylamino)carbonyl.

The term “(NZ_(C)Z_(D))carbonylalkyl” as used herein, means a(NZ_(C)Z_(D))carbonyl group, as defined herein, appended to the parentmolecular moiety through an alkyl group, as defined herein.Representative examples of (NZ_(C)Z_(D))carbonylalkyl include, but arenot limited to, (aminocarbonyl)methyl, 2-((methylamino)carbonyl)ethyland ((dimethylamino)carbonyl)methyl.

The term “(NZ_(C)Z_(D))sulfonyl” as used herein, means a —NZ_(C)Z_(D)group, as defined herein, appended to the parent molecular moietythrough a sulfonyl group, as defined herein. Representative examples of(NZ_(C)Z_(D))sulfonyl include, but are not limited to, aminosulfonyl,(methylamino)sulfonyl, (dimethylamino)sulfonyl and(ethylmethylamino)sulfonyl.

The term “oxo” as used herein, means ═O.

The term “sulfonyl” as used herein, means a —S(O)₂— group.

In Vitro Data

Determination of Inhibition Potencies

Dulbecco's modified Eagle medium (D-MEM)(with 4.5 mg/mL glucose) andfetal bovine serum were obtained from Hyclone Laboratories, Inc. (Logan,Utah). Dulbecco's phosphate-buffered saline (D-PBS)(with 1 mg/mL glucoseand 3.6 mg/l Na pyruvate)(without phenol red), L-glutamine, hygromycinB, and Lipofectamine™ were obtained from Life Technologies (GrandIsland, N.Y.). G418 sulfate was obtained from Calbiochem-NovabiochemCorp. (San Diego, Calif.). Capsaicin (8-methyl-N-vanillyl-6-nonenamide)was obtained from Sigma-Aldrich, Co. (St. Louis, Mo.). Fluo-4 AM(N-[4-[6-[(acetyloxy)methoxy]-2,7-difluoro-3-oxo-3H-xanthen-9-yl]-2-[2-[2-[bis[2-[(acetyloxy)methoxy]-2-oxyethyl]amino]-5-methylphenoxy]ethoxy]phenyl]-N-[2-[(acetyloxy)methoxy]-2-oxyethyl]-glycine,(acetyloxy)methyl ester) was purchased from Molecular Probes (Eugene,Oreg.).

The cDNAs for the human VR1 receptor were isolated by reversetranscriptase-polymerase chain reaction (RT-PCR) from human smallintestine poly A+RNA supplied by Clontech (Palo Alto, Calif.) usingprimers designed surrounding the initiation and termination codonsidentical to the published sequences (Hayes et al. Pain 88: 205-215,2000). The resulting cDNA PCR products were subcloned into pClneomammalian expression vector (Promega) and fully sequenced usingfluorescent dye-terminator reagents (Prism, Perkin-Elmer AppliedBiosystems Division) and a Perkin-Elmer Applied Biosystems Model 373 DNAsequencer or Model 310 genetic analyzer. Expression plasmids encodingthe hVR1 cDNA were transfected individually into 1321N1 humanastrocytoma cells using Lipofectamine™. Forty-eight hours aftertransfection, the neomycin-resistant cells were selected with growthmedium containing 800 μg/mL Geneticin (Gibco BRL). Surviving individualcolonies were isolated and screened for VR1 receptor activity. Cellsexpressing recombinant homomeric VR1 receptors were maintained at 37° C.in D-MEM containing 4 mM L-glutamine, 300 μg/mL G418 (Cal-biochem) and10% fetal bovine serum under a humidified 5% CO₂ atmosphere.

The functional activity of compounds at the VR1 receptor was determinedwith a Ca²⁺ influx assay and measurement of intracellular Ca²⁺ levels([Ca²⁺]i). All compounds were tested over an 11-point half-logconcentration range. Compound solutions were prepared in D-PBS (4× finalconcentration), and diluted serially across 96-well v-bottom tissueculture plates using a Biomek 2000 robotic automation workstation(Beckman-Coulter, Inc., Fullerton, Calif.). A 0.2 μM solution of the VR1agonist capsaicin was also prepared in D-PBS. The fluorescent Ca²⁺chelating dye fluo-4 was used as an indicator of the relative levels of[Ca²⁺]i in a 96-well format using a Fluorescence Imaging Plate Reader(FLIPR)(Molecular Devices, Sunnyvale, Calif.). Cells were grown toconfluency in 96-well black-walled tissue culture plates. Then, prior tothe assay, the cells were loaded with 100 μL per well of fluo-4 AM (2μM, in D-PBS) for 1-2 hours at 23° C. Washing of the cells was performedto remove extracellular fluo-4 AM (2×1 mL D-PBS per well), andafterward, the cells were placed in the reading chamber of the FLIPRinstrument. 50 μL of the compound solutions were added to the cells atthe 10 second time mark of the experimental run. Then, after a 3 minutetime delay, 50 μL of the capsaicin solution was added at the 190 secondtime mark (0.05 μM final concentration)(final volume=200 μL) tochallenge the VR1 receptor. Time length of the experimental run was 240seconds. Fluorescence readings were made at 1 to 5 second intervals overthe course of the experimental run. The peak increase in relativefluorescence units (minus baseline) was calculated from the 190 secondtime mark to the end of the experimental run, and expressed as apercentage of the 0.05 μM capsaicin (control) response. Curve-fits ofthe data were solved using a four-parameter logistic Hill equation inGraphPad Prism® (GraphPad Software, Inc., San Diego, Calif.), and IC₅₀ovalues were calculated.

The compounds of the present invention were found to be antagonists ofthe vanilloid receptor subtype 1 (VR1) receptor with IC_(50s) from 1000nM to 0.1 nM. In a preferred range, compounds tested had IC50s from 500nM to 0.1 nM. In a more preferred range, compounds tested had IC50s from50 nM to 0.1 nM.

In Vivo Data

Determination of Antinociceptive Effect

Experiments were performed on 400 adult male 129J mice (Jacksonlaboratories, Bar Harbor, Me.), weighing 20-25 g. Mice were kept in avivarium, maintained at 22° C., with a 12 hour alternating light-darkcycle with food and water available ad libitum. All experiments wereperformed during the light cycle. Animals were randomly divided intoseparate groups of 10 mice each. Each animal was used in one experimentonly and was sacrificed immediately following the completion of theexperiment. All animal handling and experimental procedures wereapproved by an IACUC Committee.

The antinociceptive test used was a modification of the abdominalconstriction assay described in Collier, et al., Br. J. Tharmacol.Chemother. 32 (1968) 295-310. Each animal received an intraperitoneal(i.p.) injection of 0.3 mL of 0.6% acetic acid in normal saline to evokewrithing. Animals were placed separately under clear cylinders for theobservation and quantification of abdominal constriction. Abdominalconstriction was defined as a mild constriction and elongation passingcaudally along the abdominal wall, accompanied by a slight twisting ofthe trunk and followed by bilateral extension of the hind limbs Thetotal number of abdominal constrictions was recorded from 5 to 20minutes after acetic acid injection. The ED_(50s) were determined basedon the i.p. injection.

The compounds of the present invention tested were found to haveantinociceptive effects with ED_(50s) from 1 mg/kg to 500 mg/kg.

The in vitro and in vivo data demonstrates that compounds of the presentinvention antagonize the VR1 receptor and are useful for treating pain.

Compounds of the present invention, as VR1 antagonists, are also usefulfor ameliorating or preventing additional disorders that are affected bythe VR1 receptors such as, but not limited to, infammatory thermalhyperalgesia, bladder overactivity, and urinary incontinence.

Compounds of the present invention, including but not limited to thosespecified in the examples, can be used to treat pain as demonstrated byNolano, M. et al., Pain 81 (1999) 135; Caterina, M. J. and Julius, D.,Annu. Rev. Neurosci. 24, (2001) 487-517; Caterina, M. J. et al., Science288 (2000) 306-313; Caterina, M. J. et al, Nature 389 (1997) 816-824.

Compounds of the present invention, including but not limited to thosespecified in the examples, can be used to treat bladder overactivityand/or urinary incontinence as demonstrated by Fowler, C. Urology 55(2000) 60.

Compounds of the present invention, including but not limited to thosespecified in the examples, can be used to treat inflammatory thermalhyperalgesia as demonstrated by Davis, J. et al., Nature 405 (2000)183-187.

The present invention also provides pharmaceutical compositions thatcomprise compounds of the present invention. The pharmaceuticalcompositions comprise compounds of the present invention that may beformulated together with one or more non-toxic pharmaceuticallyacceptable carriers.

The pharmaceutical compositions of this invention can be administered tohumans and other mammals orally, rectally, parenterally,intracistemally, intravaginally, intraperitoneally, topically (as bypowders, ointments or drops), bucally or as an oral or nasal spray. Theterm “parenterally,” as used herein, refers to modes of administrationwhich include intravenous, intramuscular, intraperitoneal, intrastemal,subcutaneous and intraarticular injection and infusion.

The term “pharmaceutically acceptable carrier,” as used herein, means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as, but not limited to, lactose, glucose andsucrose; starches such as, but not limited to, corn starch and potatostarch; cellulose and its derivatives such as, but not limited to,sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients such as, but notlimited to, cocoa butter and suppository waxes; oils such as, but notlimited to, peanut oil, cottonseed oil, safflower oil, sesame oil, oliveoil, corn oil and soybean oil; glycols; such a propylene glycol; esterssuch as, but not limited to, ethyl oleate and ethyl laurate; agar;buffering agents such as, but not limited to, magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as, but not limitedto, sodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

Pharmaceutical compositions of this invention for parenteral injectioncomprise pharmaceutically acceptable sterile aqueous or nonaqueoussolutions, dispersions, suspensions or emulsions as well as sterilepowders for reconstitution into sterile injectable solutions ordispersions just prior to use. Examples of suitable aqueous andnonaqueous carriers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol and the like), vegetable oils (such as olive oil), injectableorganic esters (such as ethyl oleate) and suitable mixtures thereof.Proper fluidity can be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms can be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid and the like. It may also be desirableto include isotonic agents such as sugars, sodium chloride and the like.Prolonged absorption of the injectable pharmaceutical form can bebrought about by the inclusion of agents which delay absorption such asaluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This can be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound may be mixed with at least one inert, pharmaceuticallyacceptable excipient or carrier, such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol and silicic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteday and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate and mixturesthereof. In the case of capsules, tablets and pills, the dosage form mayalso comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such carriers as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike.

The solid dosage forms of tablets, dragees, capsules, pills and granulescan be prepared with coatings and shells such as enteric coatings andother coatings well-known in the pharmaceutical formulating art. Theymay optionally contain opacifying agents and may also be of acomposition such that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned carriers.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan andmixtures thereof.

Besides inert diluents, the oral compositions may also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating carriers or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Compounds of the present invention can also be administered in the formof liposomes. As is known in the art, liposomes are generally derivedfrom phospholipids or other lipid substances. Liposomes are formed bymono- or multi-lamellar hydrated liquid crystals which are dispersed inan aqueous medium. Any nontoxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention, stabilizers, preservatives,excipients and the like. The preferred lipids are natural and syntheticphospholipids and phosphatidyl cholines (lecithins) used separately ortogether.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y. (1976), p. 33 et seq.

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compoundmay be mixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers or propellants which maybe required. Opthalmic formulations, eye ointments, powders andsolutions are also contemplated as being within the scope of thisinvention.

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention can be varied so as to obtain an amountof the active compound(s) which is effective to achieve the desiredtherapeutic response for a particular patient, compositions and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated and the condition and prior medical historyof the patient being treated.

When used in the above or other treatments, a therapeutically effectiveamount of one of the compounds of the present invention can be employedin pure form or, where such forms exist, in pharmaceutically acceptablesalt, ester or prodrug form. The phrase “therapeutically effectiveamount” of the compound of the invention means a sufficient amount ofthe compound to treat disorders, at a reasonable benefit/risk ratioapplicable to any medical treatment. It will be understood, however,that the total daily usage of the compounds and compositions of thepresent invention will be decided by the attending physician within thescope of sound medical judgement. The specific therapeutically effectivedose level for any particular patient will depend upon a variety offactors including the disorder being treated and the severity of thedisorder; activity of the specific compound employed; the specificcomposition employed; the age, body weight, general health, sex and dietof the patient; the time of administration, route of administration, andrate of excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or coincidental with the specificcompound employed; and like factors well known in the medical arts.

The compounds of the present invention can be used in the form ofpharmaceutically acceptable salts derived from inorganic or organicacids. The phrase “pharmaceutically acceptable salt” means those saltswhich are, within the scope of sound medical judgement, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like and arecommensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable salts are well-known in the art. Forexample, S. M. Berge et al. describe pharmaceutically acceptable saltsin detail in (J. Pharmaceutical Sciences, 1977, 66: 1 et seq). The saltscan be prepared in situ during the final isolation and purification ofthe compounds of the invention or separately by reacting a free basefunction with a suitable organic acid. Representative acid additionsalts include, but are not limited to acetate, adipate, alginate,citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,camphorate, camphorsulfonate, digluconate, glycerophosphate,hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate),lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate,oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate,pivalate, propionate, succinate, tartrate, thiocyanate, phosphate,glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, thebasic nitrogen-containing groups can be quatemized with such agents aslower alkyl halides such as, but not limited to, methyl, ethyl, propyl,and butyl chlorides, bromides and iodides; dialkyl sulfates likedimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides suchas, but not limited to, decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides; arylalkyl halides like benzyl and phenethylbromides and others. Water or oil-soluble or dispersible products arethereby obtained. Examples of acids which can be employed to formpharmaceutically acceptable acid addition salts include such inorganicacids as hydrochloric acid, hydrobromic acid, sulfuric acid, andphosphoric acid and such organic acids as acetic acid, fumaric acid,maleic acid, 4-methylbenzenesulfonic acid, succinic acid and citricacid.

Basic addition salts can be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as, but not limited to,the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptablemetal cation or with ammonia or an organic primary, secondary ortertiary amine. Pharmaceutically acceptable salts include, but are notlimited to, cations based on alkali metals or alkaline earth metals suchas, but not limited to, lithium, sodium, potassium, calcium, magnesiumand aluminum salts and the like and nontoxic quaternary ammonia andamine cations including ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine and the like. Otherrepresentative organic amines useful for the formation of base additionsalts include ethylenediamine, ethanolamine, diethanolamine, piperidine,piperazine and the like.

The term “pharmaceutically acceptable prodrug” or “prodrug,” as usedherein, represents those prodrugs of the compounds of the presentinvention which are, within the scope of sound medical judgement,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use. Prodrugs of the present invention may be rapidlytransformed in vivo to compounds of formula (I), for example, byhydrolysis in blood.

The present invention contemplates compounds of formula I formed bysynthetic means or formed by in vivo biotransformation of a prodrug.

The compounds of the invention can exist in unsolvated as well assolvated forms, including hydrated forms, such as hemihydrates. Ingeneral, the solvated forms, with pharmaceutically acceptable solventssuch as water and ethanol among others are equivalent to the unsolvatedforms for the purposes of the invention.

The total daily dose of the compounds of this invention administered toa human or lower animal may range from about 0.01 to about 100mg/kg/day. For purposes of oral administration, more preferable dosescan be in the range of from about 0.1 to about 25 mg/kg/day. If desired,the effective daily dose can be divided into multiple doses for purposesof administration; consequently, single dose compositions may containsuch amounts or submultiples thereof to make up the daily dose.

Compounds of the present invention were named by ACD/ChemSketch version5.0 (developed by Advanced Chemistry Development, Inc., Toronto, ON,Canada) or were given names which appeared to be consistent with ACDnomenclature.

Abbreviations

Abbreviations which have been used in the descriptions of the Schemesand the Examples that follow are: dba for dibenzylideneacetone; DBU for1,8-diazabicyclo[5.4.0]undec-7-ene; BINAP for2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; DCC for1,3-dicyclohexylcarbodiimide; DIEA for diisopropylethylamine; DMAP for4-dimethylaminopyridine; DMF for N,N-dimethylformamide; DMSO fordimethylsulfoxide; EDCI or EDC for1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride; HMPA forhexamethylphosphoramide; HPLC high pressure liquid chromatography; NBSfor N-bromosuccinimide; Pd for palladium; Ph for phenyl; psi for poundsper square inch; and THF for tetrahydrofuran.

Preparation of Compounds of the Present Invention

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic Schemes andExamples which illustrate a means by which the compounds of the presentinvention can be prepared.

Ureas of general formula (4), wherein R₁, R₂, R₄, R₅, R₆, R₇, R₉, and Lare as defined in formula (I), may be prepared as described in Scheme 1.5-Aminoisoquinolines of general formula (1), purchased commercially orprepared using standard chemistry known to those in the art, can betreated with trichloroacetyl chloride and a base such as, but notlimited to, triethylamine in a solvent such as dichloromethane toprovide trichloroacetamides of general formula (2). Trichloroacetamidesof general formula (2) can be treated with amines of general formula (3)and a non-nucleophilic base such as, but not limited to, DBU in asolvent such as, but not limited to, acetonitrile to provide ureas ofgeneral formula (4).

Carbamates of general formula (6), wherein R₁, R₂, R₄, R₅, R₆, R₇, R₉and L are as defined in formula (1), may also be prepared as describedin Scheme 1. Trichloroacetamides of general formula (2) can be treatedwith alcohols of general formula (5) and a non-nucleophilic base suchas, but not limited to, DBU in a solvent such as, but not limited to,acetonitrile to provide carbamates of general formula (6).

Ureas of general formula (4), wherein R₁, R₂, R₄, R₅, R₆, R₇, R₉, and Lare as defined in formula (1), may be prepared as described in Scheme 2.Amines of general formula (3) can be treated with phosgene ortriphosgene and DMAP in a solvent such as, but not limited to,dichloromethane to provide isocyanates of general formula (8).5-Aminoisoquinolines of general formula (1) can be treated withisocyanates of general formula (8) in a solvent such as, but not limitedto, toluene or THF or a combination thereof to provide ureas of generalformula (4).

Ureas of general formula (4), wherein R₁, R₂, R₄, R₅, R₆, R₇, R₉, and Lare as defined in formula (1), may be prepared as described in Scheme 3.5-Aminoisoquinolines of general formula (1) can be treated with phosgeneor triphosgene and DMAP in a solvent such as, but not limited to,dichloromethane to provide isocyanates of general formula (10).Isocyanates of general formula (10) can be treated with amines ofgeneral formula (3) in a solvent such as, but not limited to, toluene orTHF or a combination thereof to provide ureas of general formula (4).

Ureas of general formula (13), wherein R₁, R₂, R₅, R₆, R₇, R₉, and L areas defined in formula (1), and carbamates of general formula (14),wherein R₁, R₂, R₅, R₆, R₇, R₉ and L are as defined in formula (I), maybe prepared as described in Scheme 4. 5-Aminocinnolines of generalformula (12), purchased commercially or prepared using standardchemistry known to those in the art, may be processed as described inSchemes 1-3 to provide ureas of general formula (13) and carbamates ofgeneral formula (14).

Ureas of general formula (16), wherein R₁, R₃, R₄, R₅, R₆, R₇, R₉ and Lare as defined in formula (1), and carbamates of general formula (17),wherein R₁, R₃, R₄, R₅, R₆, R₇, R₉ and L are as defined in formula (I),may be prepared as described in Scheme 4. 8-Aminoisoquinolines ofgeneral formula (15), purchased commercially or prepared using standardchemistry known to those in the art, may be processed as described inSchemes 1-3 to provide ureas of general formula (16) and carbamates ofgeneral formula (17).

Ureas of general formula (20), wherein R₁, R₂, R₃, R₅, R₆, R₇, R₉, and Lare as defined in formula (I), and carbamates of general formula (21),wherein R₁, R₂, R₃, R₅, R₆, R₇, R₉, and L are as defined in formula(21), may be prepared as described in Scheme 5. 4-Aminoindoles ofgeneral formula (19), purchased commercially or prepared using standardchemistry known to those in the art, may be processed as described inSchemes 1-3 to provide ureas of general formula (20) and carbamates ofgeneral formula (21).

Ureas of general formula (23), wherein R₁, R₃, R₅, R₆, R₇, R₄ and L areas defined in formula (I), and carbamates of general formula (24),wherein R₁, R₃, R₅, R₆, R₇, R₉, and L are as defined in formula (I), maybe prepared as described in Scheme 5. 4-Aminoindazoles of generalformula (22), purchased commercially or prepared using standardchemistry known to those in the art, may be processed as described inSchemes 1-3 to provide ureas of general formula (23) and carbamates ofgeneral formula (24).

Amides of general formula (32), wherein R₁, R₂, R₄, R₅, R₆, R₇, R₉, andL are as defined in formula (I), can be prepared as described in Scheme6. Amines of general formula (1) can be treated with an acid such as,but not limited to, concentrated sulfuric acid and N-bromosuccinimide toprovide bromides of general formula (27). Bromides of general formula(27) can be treated with an organolithium reagent such as, but notlimited to, n-butyllithium and diethyl oxalate in a solvent such as, butnot limited to, THF to provide keto esters of general formula (28). Ketoesters of general formula (28) can be treated with a reducing agent suchas, but not limited to, 10% Pd/C under a hydrogen atmosphere (50 psi) ina solvent such as, but not limited to, ethanol to provide hydroxy estersof general formula (29). Hydroxy esters of general formula (29) can betreated with an acid chloride such as, but not limited to, acetylchloride in a solvent such as, but not limited to, pyridine to providediesters of general formula (30). Diesters of general formula (30) canbe treated with 10% Pd/C and a base such as, but not limited to,triethylamine under a hydrogen atmosphere (60 psi) in a solvent such as,but not limited to, ethanol to provide esters of general formula (31).Esters of general formula (31) can be treated with amines of generalformula (3) to provide amides of general formula (32). Alternatively,esters of general formula (31) can be treated with aqueous base such as,but not limited to, aqueous sodium hydroxide or aqueous potassiumhydroxide to provide the acids which can then be converted into amidesof general formula (32) by treatment with amines of general formula (3)under standard DCC or EDCI coupling procedures that are well known inthe art.

Esters of general formula (33), wherein R₁, R₂, R₄, R₅, R₆, R₇, R₉ and Lare as defined in formula (I), can be prepared as described in Scheme 6.Esters of general formula (31) can be treated with alcohols of generalformula (5) under standard transesterification conditions well known tothose of skill in the art to provide esters of general formula (33).

The following Examples are intended as an illustration of and not alimitation upon the scope of the invention as defined in the appendedclaims.

EXAMPLE 1 N-[2-(3-fluorophenyl)ethyl]-N′-isoquinolin-5-ylurea EXAMPLE 1A2,2,2-trichloro-N-isoquinolin-5-ylacetamide

A solution of 5-aminoisoquinoline (1.0 g, 6.9 mmol) in dichloromethane(40 mL) and Et₃N (1 mL) at 5° C. was treated with trichloroacetylchloride (1.38 g, 7.6 mmol) dropwise. The reaction mixture was stirredat ambient temperature for 14 hours, concentrated, diluted with ethylacetate and washed with 1N HCl. The aqueous layer was treated withaqueous NaHCO₃ and extracted with ethyl acetate. The organic layer thewas washed with water and concentrated. The solid residue was suspendedin ethyl acetate (5 mL) and filtered to obtain 1.3 g (65%) of the titlecompound as a tan solid. ¹H NMR (300 MHz, d₆-DMSO) δ 11.20 (broad s,1H), 9.41, (s, 1H), 8.60 (d, 1H), 8.18 (m, 1H), 7.77 (m, 2H), 7.77 (d,1H); MS (DCI/NH₃) m/z 289 (M+H)⁺.

EXAMPLE 1B N-[2-(3-fluorophenyl)ethyl]-N′-isoquinolin-5-ylurea

The product from Example 1A (0.65 g, 2.25 mmol), DBU (0.85 g, 5.6 mmol)and 2-(3-fluorophenyl)ethylamine (0.35 g, 2.5 mmol) in acetonitrile (50mL) were refluxed for 10 hours. The mixture was cooled, concentrated,diluted with ethyl acetate, washed twice with aqueous ammonium chlorideand concentrated to dryness. The solid obtained was suspended in ethylacetate and filtered to obtain 0.45 g (65%) of the title compound as atan solid. ¹H NMR (300 MHz, d₆-DMSO) δ 9.27 (s, 1H), 8.63 (s, 1H), 8.51(d, 1H), 8.26 (d, 1H), 7.89 (d, 1H), 7.71.(d, 1H), 7.59 (m, 1H), 7.35(m, 1H), 7.18-7.0 (m, 3H), 6.60 (t, 1H), 3.42 (m, 2H), 2.72 (m, 2H); MS(DCl/NH₃) m/z 310 (M+H)⁺; Anal. Calcd. For C₁₈H₁₆N₃FO. 0.1H₂O: C, 69.48;H, 5.25; N, 13.51. Found: C, 69.31; H, 5.25; N, 13.46.

EXAMPLE 2 N-[2-(3-bromophenyl)ethyl]-N′-isoquinolin-5-ylurea

The title compound was prepared using 2-(3-bromophenyl)ethylamine, DBU,the product from Example 1A and the procedure described in Example 1B.¹H NMR (300 MHz, d₆-DMSO) δ 9.26 (s, 1H), 8.63 (s, 1H), 8.51 (d, 1H),8.23 (d, 1H), 7.90 (d, 1H), 7.71 (d, 1H), 7.59 (m, 1H), 7.40 (m, 2H),7.29 (m, 2H), 6.60 (t, 1H), 3.42 (m, 2H), 2.80 (m, 2H); MS (DCI/NH₃) m/z370 (M+H)⁺; Anal. Calcd. For C₁₈H₁₆N₃BrO: C, 58.39; H, 4.36; N, 11.35.Found: C, 58.17; H, 4.46; N, 11.28.

EXAMPLE 3 N-isoquinolin-5-yl-N′-[4-(trifluoromethyl)benzyl]urea

The title compound was prepared using 4-(trifluoromethyl)benzylamine,DBU, the product from Example 1A and the procedure described in Example1B. ¹H NMR (300 MHz, d₆-DMSO) 9.26 (s, 1H), 8.82 (s, 1H), 8.52 (d, 1H),8.26 (d, 1H), 7.94 (d, 1H), 7.71 (m, 3H), 7.58 (m, 3H), 7.20 (t, 1H),4.48 (d, 2H); MS (DCI/NH₃) m/z 346 (M+H)⁺; Anal. Calcd. For C₁₈H₁₄N₃F₃O.0.05H₂O: C, 62.63; H, 4.19; N, 12.04. Found: C, 62.41; H, 4.58; N,11.44.

EXAMPLE 4 N-isoquinolin-5-yl-N′-(4-phenoxybenzyl)urea

The title compound was prepared using 4-phenoxybenzylamine, DBU, theproduct from Example 1A and the procedure described in Example 1B. ¹HNMR (300 MHz, d₆-DMSO) δ 9.30 (s, 1H), 8.75 (s, 1H), 8.58 (d, 1H), 8.31(d, 1H), 7.92 (d, 1H), 7.75 (d, 1H), 7.60 (t, 1H), 7.40 (m, 4H),7.18-6.95 (m, 6H), 4.38 (d, 2H); MS (DCI/NH₃) m/z 369 (M+H)⁺.

EXAMPLE 5 N-[3-fluoro-5-(trifluoromethyl)benzyl]-N′-isoquinolin-5-ylurea

The title compound was prepared using3-fluoro-5-(trifluoromethyl)benzylamine, DBU, the product from Example1A and the procedure described in Example 1B. ¹H NMR (300 MHz, d₆-DMSO)δ 9.28 (s, 1H), 8.88 (s, 1H), 8.53 (d, 1H),8.22 (d, 1H), 7.90 (d, 1H),7.77 (d, 1H), 7.55 (m, 4H), 7.20 t, 1H), 4.45 (d, 2H); MS (DCI/NH) m/z364 (M+H)⁺.

EXAMPLE 6 N-(2,5-dichlorobenzyl)-N′-isoquinolin-5-ylurea

The title compound was prepared using 2,5-dichlorobenzylamine, DBU, theproduct from Example 1A and the procedure described in Example 1B. ¹HNMR (300 MHz, d₆-DMSO) δ 9.30 (s, 1H), 8.90 (broad s, 1H), 8.55 (d, 1H),8.36 (d, 1H), 7.97 (d, 1H), 7.76 (d, 1H), 7.61-7.13 (m, 5H), 4.43 (d,2H); MS (DCI/NH₃) m/z 345 (M+H)⁺; Anal. Calcd. For C₁₇H₁₃N₃Cl₂O: 0.2H₂O:C, 58.07; H, 3.90; N, 11.95. Found: C, 57.76; H, 3.84; N, 11.64.

EXAMPLE 7 N-(1,3-benzodioxol-5-ylmethyl)-N′-isoquinolin-5-ylurea

The title compound was prepared using 1,3-benzodioxol-5-ylmethylamine,DBU, the product from Example 1A and the procedure described in Example1B. ¹H NMR (300 MHz, d₆-DMSO) δ 9.27 (s, 1H), 8.85 (broad s, 1H), 8.50(d, 1H), 8.30 (d, 1H), 8.00 (d, 1H), 7.73 (d, 1H), 7.60 t, 1H), 7.15 (m,2H), 6.89 (m, 2H), 6.00 (s, 2H), 4.28 (d, 2H); MS (DCI/NH) m/z 322(M+H)⁺; Anal. Calcd. For C₁₇H₁₃N₃O. 0.5H₂O.0.8NH₄Cl: C, 57.94; H, 5.19;N, 14.26. Found: C, 57.63; H, 5.14; N, 14.41.

EXAMPLE 8 N-[2-(4-fluorophenyl)ethyl]-N′-isoquinolin-5-ylurea

The title compound was prepared using 2-(4-fluorophenyl)ethylamine, DBU,the product from Example 1A and the procedure described in Example 1B.¹H NMR (300 MHz, d₆-DMSO) δ 9.25 (s, 1H), 8.70 (broad s, 1H), 8.50 (d,1H), 8.27 (d, 1H), 7.93 (d, 1H), 7.71 (d, 1H), 7.60 (t, 1H), 7.30 (m,2H), 7.13 (m, 2H), 6.70 (t, 1H), 3.40 (m, 2H), 2.80 (m, 2H); MS(DCI/NH₃) m/z 310 (M+H)⁺; Anal. Calcd. For C₁₇H₁₃N₃FO. 0.1H₂O.0.2NH₄Cl:C, 67.18; H, 5.32; N 13.93. Found: C, 66.86; H, 5.41; N, 13.75.

EXAMPLE 9 N-(3-bromobenzyl)-N′-isoquinolin-5-ylurea

The title compound was prepared using 3-bromobenzylamine, DBU, theproduct from Example 1A and the procedure described in Example 1B. ¹HNMR (300 MHz, d₆-DMSO)δ 9.29 (s, 1H), 8.80 (broad s, 1H), 8.53 (d, 1H),8.25 (d, 1H), 7.93 (d, 1H), 7.77 (d, 1H), 7.58 (m, 2H), 7.48 (m, 1H),7.30 (m, 2H), 7.10 (t, 1H), 4.39 (d, 2H); MS (DCI/NH₃) m/z 356 (M+H)⁺;Anal. Calcd. For C₁₇H₁₄N₃BrO: C, 57.32; H, 3.96; N, 11.80. Found: C,57.06; H, 3.90; N, 11.45.

EXAMPLE 10 N-[2-(3,4-dimethylphenyl)ethyl]-N′-isoquinolin-5-ylurea

The title compound was prepared using 2-(3,4-dimethylphenyl)ethylamine,DBU, the product from Example 1A and the procedure described in Example1B. ¹H NMR (300 MHz, d₆-DMSO) δ 9.25 (s, 1H), 8.68 (broad s, 1H), 8.50(d, 1H), 8.28 (d, 1H), 7.90 (d, 1H), 7.70 (d, 1H), 7.57 (t, 1H), 7.00(m, 3H), 6.60 (t, 1H), 3.40 m, 2H), 2.71 (m, 2H), 2.19 (s, 3H), 2.16 (s,3H); MS (DCI/NH₃) m/z 320 (M+H)⁺; Anal. Calcd. For C₂₀H₂₁N₃O.0.3H₂O: C,73.96; H, 6.70; N, 12.94. Found: C, 73.80; H, 6.32; N, 12.98.

EXAMPLE 11 N-[1-(4-bromophenyl)ethyl]-N′-isoquinolin-5-ylurea

5-Aminoisoquinoline (0.64 g, 4.42 mmol) in dichloromethane (20 mL) wastreated with 1-bromo-4-(1-isocyanatoethyl)benzene (1.0 g, 4.42 mmol) intoluene (10 mL). The mixture was stirred 14 hours at ambient temperatureand filtered to obtain 1.2 g (74%) of the product as light grey solid.¹H NMR (300 MHz, d₆-DMSO) δ 9.28 (s, 1H), 8.68 (broad s, 1H), 8.56 (d,1H), 7.90 (d, 1H), 7.72 (d, 1H) 7.59 (m, 2H), 7.35 (m, 2H), 7.10 (d,1H), 4.85 (m, 1H), 1.40 (d, 3H); MS (DCI/NH₃) m/z 370 (M+H)⁺; Anal.Calcd. For C₁₈H₁₆N₃BrO.0.1H₂O: C, 58.11; H, 4.39; N, 11.29. Found: C,57.79; H, 4.21; N, 11.16.

EXAMPLE 12 4-(trifluoromethyl)benzyl isoquinolin-5-ylcarbamate

The title compound was prepared using[4-(trifluoromethyl)phenyl]methanol, DBU, the product from Example 1Aand the procedure described in Example 1B. ¹H NMR (300 MHz, d₆-DMSO) δ9.90 (broad s, 1H), 9.30 (s, 1H), 8.52 (d, 1H), 7.94 (m, 3H), 7.80 d,2H), 7.70 (m, 3H), 5.30 (s, 2H); MS (DCI/NH₃) m/z 347 (M+H)⁺; Anal.Calcd. For C₁₈H₁₃N₂O₂F₃: C, 62.43; H, 3.78; N, 8.09. Found: C, 62.23; H,3.83; N, 7.99.

EXAMPLE 13 2-(3-bromophenyl)ethyl isoquinolin-5-ylcarbamate

The title compound was prepared using 2-(3-bromophenyl)ethanol, DBU, theproduct from Example 1A and the procedure described in Example 1B. ¹HNMR (300 MHz, d₆-DMSO) δ 9.70 (broad s, 1H), 9.30 (s, 1H), 8.50 (d, 1H),7.88 (m, 3H), 7.64 (t, 1H), 7.56 (s, 1H), 7.45 (m, 1H), 7.30 (m, 2H),4.34 (t, 2H), 3.00 (t, 2H); MS (DCI/NH₃) m/z 371 (M+H)⁺; Anal. Calcd.For C₁₈H₁₅N₂O₂Br: C, 58.24; H, 4.07; N, 7.55. Found: C, 58.35; H, 4.07;N, 7.51.

EXAMPLE 14 1-naphthylmethyl isoquinolin-5-ylcarbamate

The title compound was prepared using 1-naphthylmethanol, DBU, theproduct from Example 1A and the procedure described in Example 1B. ¹HNMR (DMSO-d₆) δ 9.85 (s, 1H), 9.31 (s, 1H), 8.48 (d, 1H), 8.15 (d, 1H),8.04-7.91 (m, 5H), 7.72-7.52 (m, 5H), 5.69 (s, 2H); MS (ESI+) m/z 328(M+H)⁺; Anal. Calcd. For C₂₁H₁₆N₂O₂: C, 76.81, H, 4.91, N, 8.53; Found:C, 76.64, H, 4.73, N, 8.29.

EXAMPLE 15 N-isoquinolin-5-yl-N′-[4-(trifluoromethoxy)benzyl]urea

The title compound was prepared using 4-(trifluoromethoxy)benzylamine,DBU, the product from Example 1A and the procedure described in Example1B. MS (ESI+) m/z 362 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 4.41 (d, 2H), 7.14 (t,1H), 7.35 (d, 2H), 7.48 (d, 2H), 7.60 (t, 1H), 7.75 (d, 1H), 7.95 (d,1H), 8.28 (d, 1H), 8.53 (d, 1H), 8.79 (s, 1H), 9.27 (s, 1H).

EXAMPLE 16 N-(3,4-dichlorobenzyl)-N′-(3-methylcinnolin-5-yl)urea EXAMPLE16A 2,2,2-trichloro-N-(3-methylcinnolin-5-yl)acetamide

The title compound was prepared using 3-methylcinnolin-5-amine(commercially available, Maybridge), triethylamine, trichloroacetylchloride and the procedure described in Example 1A.

EXAMPLE 16B N-(3,4-dichlorobenzyl)-N′-(3-methylcinnolin-5-yl)urea

The title compound was prepared using 3,4-dichlorobenzylamine, theproduct from Example 16A, DBU and the procedure described in Example 1B.MS (ESI+) m/z 362 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 2.88 (s, 3H), 4.36 (d, 2H),7.10 (t, 1H), 7.34 (dd, 1H), 7.59 (m, 2H), 7.76 (t, 1H), 8.04 (d, 2H),8.19 (d, 1H), 8.93 (s, 1H).

EXAMPLE 17 N-isoquinolin-5-yl-N′-(4-methylbenzyl)urea

The title compound was prepared using 4-methylbenzylamine, the productfrom Example 1A, DBU and the procedure described in Example 1B. MS(ESI+) m/z 292 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 2.29 (s, 3H), 4.33 (d, 2H),7.00 (t, 1H), 7.17 (d, 2H), 7.24 (d, 2H), 7.60 (t, 1H), 7.73 (d, 1H),7.93(d, 1H), 8.30 (d, 1H), 8.53 (d, 1H), 8.70 (s, 1H), 9.26 (s, 1H).

426934 EXAMPLE 18 N-(4-fluorobenzyl)-N′-isoquinolin-5-ylurea

The title compound was prepared using 4-fluorobenzylamine, the productfrom Example 1A, DBU and the procedure described in Example 1B. MS(APCI+) m/z 296 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 4.37 (d, 2H), 7.07 (t, 1H),7.18 (t, 2H), 7.40 (dd, 2H), 7.60 (t, 1H), 7.74 (d, 1H), 7.94 (d, 1H),8.28 (d, 1H), 8.54 (d, 1H), 8.74 (s, 1H), 9.27 (s, 1H).

EXAMPLE 19 N-isoquinolin-5-yl-N′-[(trans)-2-phenylcyclopropyl]urea

The title compound was prepared using trans 2-phenylcyclopropylaminehydrochloride, the product from Example 1A, DBU and the proceduredescribed in Example 1B. MS (ESI+) m/z 304 (M+H)⁺; ¹H NMR (DMSO-d₆) δ1.21 (m, 2H), 2.05 (m, 1H), 2.82 (m, 1H), 7.00 (d, 1H), 7.17 (t, 3H),7.27 (t, 2H), 7.60 (t, 1H), 7.74 (d, 1H), 7.88 (d, 1H), 8.26 (d, 1H),8.53 (d, 1H), 8.57 (s, 1H), 9.27 (s, 1H).

EXAMPLE 20 N-[2-(3,4-dichlorophenyl)ethyl]-N′-isoquinolin-5-ylurea

The title compound was prepared using 2-(3,4-dichlorophenyl)ethylamine,the product from Example 1A, DBU and the procedure described in Example1B. MS (ESI+) m/z 361 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 2.82 (t, 2H), 3.43 (q,2H), 6.63 (t, 1H), 7.29 (dd, 1H), 7.59 (m, 3H), 7.73 (d, 1H), 7.88 (d,1H), 8.23 (d, 1H), 8.52 (d, 1H), 8.65 (s, 1H), 9.26 (s, 1H).

EXAMPLE 21 N-[2-(3,5-dimethoxyphenyl)ethyl]-N′-isoquinolin-5-ylurea

The title compound was prepared using 2-(3,5-dimethoxyphenyl)ethylamine,the product from Example 1A, DBU and the procedure described in Example1B. MS (ESI+) m/z 352 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 2.74 (t, 2H), 3.42 (q,2H), 3.73 (s, 6H), 6.36 (t, 1H), 6.44 (d, 2H), 6.59 (t, 1H), 7.59 (t,1H), 7.72 (d, 1H), 7.91 (d, 1H), 8.27 (d, 1H), 8.52 (d, 1H), 8.67 (s,1H), 9.26 (s, 1H).

EXAMPLE 22 N-(4-chlorobenzyl)-N′-isoquinolin-5-ylurea

The title compound was prepared using 4-chlorobenzylamine, the productfrom Example 1A, DBU and the procedure described in Example 1B. MS(ESI+) m/z 313 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 4.37 (d, 2H), 7.14 (t, 1H),7.40 (q, 4H), 7.60 (t, 1H), 7.74 (d, 1H), 7.95 (d, 1H), 8.28 (dd, 1H),8.53 (d, 1H), 8.80 (s, 1H), 9.27 (s, 1H).

EXAMPLE 23N-isoquinolin-5-yl-N′-{2-[3-(trifluoromethyl)phenyl]ethyl}urea

The title compound was prepared using2-[3-(trifluoromethyl)phenyl]ethylamine, the product from Example 1A,DBU and the procedure described in Example 1B. MS (ESI+) m/z 360 (M+H)⁺;¹H NMR (DMSO-d₆) δ 2.91 (t, 2H), 3.46 (q, 2H), 6.62 (t, 1H), 7.59 (m,4H), 7.64 (s, 1H), 7.73 (d, 1H), 7.87 (d, 1H), 8.23 (d, 1H), 8.51 (d,1H), 8.64 (s, 1H), 9.26 (s, 1H).

EXAMPLE 24 N-[2-(2,6-dichlorophenyl)ethyl]-N′-isoquinolin-5-ylurea

The title compound was prepared using 2-(2,6-dichlorophenyl)ethylamine,the product from Example 1A, DBU and the procedure described in Example1B. MS (ESI+) m/z 361 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 3.12 (t, 2H), 3.40 (q,2H), 6.72 (t, 1H), 7.28 (t, 1H), 7.46 (d, 2H), 7.58 (t, 1H), 7.72 (d,1H), 7.87 (d, 1H), 8.19 (d, 1H), 8.51 (d, 1H), 8.60 (s, 1H), 9.25 (s,1H).

EXAMPLE 25 N-[2-(2,3-dichlorophenyl)ethyl]-N′-isoquinolin-5-ylurea

The title compound was prepared using 2-(2,3-dichlorophenyl)ethylamine,the product from Example 1A, DBU and the procedure described in Example1B. MS (ESI+) m/z 361 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 3.01 (t, 2H), 3.46 (q,2H), 6.67 (t, 1H), 7.34 (t, 1H), 7.38 (dd, 1H), 7.53 (dd, 1H), 7.59 (t,1H), 7.74 (d, 1H), 7.87 (d, 1H), 8.21 (d, 1H), 8.52 (d, 1H), 8.64 (s,1H), 9.26 (s, 1H).

EXAMPLE 26 N-isoquinolin-5-yl-N′-[3-(trifluoromethoxy)benzyl]urea

The title compound was prepared using 3-(trifluoromethoxy)benzylamine,the product from Example 1A, DBU and the procedure described in Example1B. MS (ESI+) m/z 362 (M+H)⁺; ¹H NMR (DMSO-d₆)δ 4.44 (d, 2H), 7.15 (t,1H), 7.26 (d, 1H), 7.34 (s, 1H), 7.40 (d, 1H), 7.50 (t, 1H), 7.61 (t,1H), 7.76 (d, 1H), 7.95 (d, 1H), 8.25 (d, 1H), 8.53 (d, 1H), 8.80 (s,1H), 9.28 (s, 1H).

EXAMPLE 27 N-[2-(4-ethoxy-3-methoxyphenyl)ethyl]-N′-isoquinolin-5-ylurea

The title compound was prepared using2-(4-ethoxy-3-methoxyphenyl)ethylamine, the product from Example 1A, DBUand the procedure described in Example 1B. MS (ESI+) m/z 366 (M+H)⁺; ¹HNMR (DMSO-d₆) δ 1.31 (t, 3H), 2.73 (t, 2H), 3.40 (q, 2H), 3.76 (s, 3H),3.97 (q, 2H), 6.62 (t, 1H), 6.76 (dd, 1H), 6.87 (d, 2H), 7.59 (t, 1H),7.72 (d, 1H), 7.93 (d, 1H), 8.28 (d, 1H), 8.52 (d, 1H), 8.69 (s, 1H),9.26 (s, 1H).

EXAMPLE 28 N-[2-(2,4-dichlorophenyl)ethyl]-N′-isoquinolin-5-ylurea

The title compound was prepared using 2-(2,4-dichlorophenyl)ethylamine,the product from Example 1A, DBU and the procedure described in Example1B. ¹H NMR (DMSO-d₆) δ 9.26 (s, 1H); 8.62 (s, 1H); 8.53 (d, 1H); 8.22(dd, 1H); 7.88 (d, 1H); 7.74 (d, 1H); 7.61 (m, 1H); 7.57 (d, 1H); 7.42(m, 2H); 6.64 (t, 1H); 3.43 (q, 2H); 2.93 (t, 2H).

EXAMPLE 29 N-(3-bromo-4-fluorobenzyl)-N′-isoquinolin-5-ylurea

The title compound was prepared using 3-bromo-4-fluorobenzylamine, theproduct from Example 1A, DBU and the procedure described in Example 1B.MS (ESI+) m/z 376 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 9.55 (s, 1H); 9.06 (s, 1H);8.64 (d, 1H); 8.42 (d, 1H); 8.25 (d, 1H); 7.95 (d, 1H); 7.76 (t, 1H);7.70 (dd, 1H); 7.38 (m, 2H); 7.15 (m, 2H); 4.35 (d, 2H).

EXAMPLE 30 N-(3,4-dimethylbenzyl)-N′-isoquinolin-5-ylurea

The title compound was prepared using 3,4-dimethylbenzylamine, theproduct from Example 1A, DBU and the procedure described in Example 1B.MS (ESI+) m/z 307 M+H)⁺; ¹H NMR (DMSO-d₆) δ 9.55 (s, 1H); 8.98 (s, 1H);8.62 (d, 1H); 8.46 (d, 1H); 8.25 (d, 1H); 7.94 (d, 1H); 7.78 (t, 1H);7.08 (m, 3H); 6.95 (m, 2H); 4.30 (d, 2H); 2.20 (s, 3H); 2.18 (s, 3H).

EXAMPLE 31 N-isoquinolin-5-yl-N′-(3-phenylpropyl)urea

The title compound was prepared using 3-phenylpropylamine, the productfrom Example 1A, DBU and the procedure described in Example 1B. MS(ESI+) m/z 306 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 9.61 (s, 1H); 9.05 (s, 1H);8.65 (d, 1H); 8.50 (d, 1H); 8.40 (d, 1H); 7.96 (d, 1H); 7.80 (t, 1H);7.21 (m, 6H); 6.92 (t, 1H); 3.18 (q, 2H); 2.65 (t, 2H); 1.78 (m, 2H).

EXAMPLE 32 N-(3,5-dichlorobenzyl)-N′-isoquinolin-5-ylurea

The title compound was prepared using 3,5-dichlorobenzylamine, theproduct from Example 1A, DBU and the procedure described in Example 1B.MS (ESI+) m/z 347 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 9.60 (s, 1H); 9.18 (s, 1H);8.65 (d, 1H); 8.44 (d, 1H); 8.35 (d, 1H); 7.96 (d, 1H); 7.80 (t, 1H);7.43 (dt, 1H); 7.40 (m, 2H); 7.35 (m, 1H); 7.25 (d, 1H); 4.40 (d, 2H).

432465 EXAMPLE 33 N-(3-chloro-4-methylbenzyl)-N′-isoquinolin-5-ylurea

The title compound was prepared using 3-chloro-4-methylbenzylamine, theproduct from Example 1A, DBU and the procedure described in Example 1B.MS (ESI+) m/z 326 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 9.65 (s, 1H); 9.20 (s, 1H);8.65 (d, 1H); 8.50 (d, 1H); 8.40 (d, 1H); 8.00 (d, 1H); 7.80 (t, 1H);7.30 (m, 5H); 4.35 (d, 2H); 2.30 (s, 3H).

EXAMPLE 34 N-isoquinolin-5-yl-N′-(2-phenoxyethyl)urea

The title compound was prepared using 2-phenoxyethylamine, the productfrom Example 1A, DBU and the procedure described in Example 1B. MS(ESI+) m/z 308 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 9.50 (s, 1H); 8.98 (s, 1H);8.61 (d, 1H); 8.45 (d, 1H); 8.20 (d, 1H); 7.90 (d, 1H); 7.75 (t, 1H);7.26 (m, 3H); 6.95 (m, 4H); 4.00 (t, 2H); 3.50 (m, 2H).

EXAMPLE 35 N-(3,4-dichlorobenzyl)-N′-isoquinolin-5-ylurea

The title compound was prepared using 3,4-dichlorobenzylamine, theproduct from Example 1A, DBU and the procedure described in Example 1B.MS (ESI−) m/z 344 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ 9.27 (s, 1H), 8.82(bs, 1H), 8.54 (d, 1H), 8.25 (m, 1H), 7.94 (d, 1H), 7.76 (d, 1H),7.56-7.65 (m, 3H), 7.35 (m, 1H), 7.15 (t, 1H), 4.38 (d, 2H); Anal. Calcdfor C₁₇H₁₃Cl₂N₃O: C, 58.98; H, 3.78; N, 12.14. Found: C, 59.02; H, 3.70;N, 12.10.

EXAMPLE 36 N-(3-fluorobenzyl)-N′-isoquinolin-5-ylurea

The title compound was prepared using 3-fluorobenzylamine, the productfrom Example 1A, DBU and the procedure described in Example 1B. MS(ESI−) m/z 294 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ 9.28 (s, 1H), 8.80(bs, 1H), 8.54 (d, 1H), 8.28 (m, 1H), 7.95 (d, 1H), 7.76 (d, 1H), 7.60(t, 1H), 7.35-7.45 (m, 1H), 7.05-7.15 (m, 4H), 4.40 (d, 2H); Anal. Calcdfor C₁₇H₁₄FN₃O: C, 69.14; H, 4.78; N, 14.23. Found: C, 68.98; H, 4.83;N, 14.27.

EXAMPLE 37 N-(4-tert-butylbenzyl)-N′-isoquinolin-5-ylurea

The title compound was prepared using 4-tert-butylbenzylamine, theproduct from Example 1A, DBU and the procedure described in Example 1B.MS (ESI+) m/z 334 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 9.26 (s, 1H), 8.70(bs, 1H), 8.53 (d, 1H), 8.31 (dd, 1H), 7.92 (d, 1H), 7.73 (d, 1H), 7.60(t, 1H), 7.38 (m, 2H), 7.28 (m, 2H), 7.01 (t, 1H), 4.32 (d, 2H), 1.27(s, 9H). Anal. Calcd for C₂₁H₂₃N₃O.0.3 H₂O: C, 74.44; H, 7.02; N, 12.40.Found: C, 74.19; H, 6.88; N, 12.33.

EXAMPLE 38 N-isoquinolin-5-yl-N′-[2-(3-methylphenyl)ethyl]urea

The title compound was prepared using 2-(3-methylphenyl)ethylamine, theproduct from Example 1A, DBU and the procedure described in Example 1B.MS (ESI+) m/z 306 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 9.26 (m, 1H), 8.66(bs, 1H), 8.52 (d, 1H), 8.28 (dd, 1H), 7.90 (d, 1H), 7.72 (d, 1H), 7.59(t, 1H), 7.21 (t, 1H), 7.00-7.11 (m, 3H), 6.60 (t, 1H), 3.41 (m, 2H),2.76 (t, 2H), 2.30 (s, 3H); Anal. Calcd for C₁₉H₁₉N₃O.0.1 H₂O: C, 74.29;H, 6.30; N, 13.68. Found: C, 74.06; H, 6.43; N, 13.76.

EXAMPLE 39 N-isoquinolin-5-yl-N′-[2-(4-methylphenyl)ethyl]urea

The title compound was prepared using 2-(3-methylphenyl)ethylamine, theproduct from Example 1A, DBU and the procedure described in Example 1B.MS (ESI+) m/z 306 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 9.26 (s, 1H), 8.66(bs, 1H), 8.52 (d, 1H), 8.28 (m, 1H), 7.90 (d, 1H), 7.72 (d, 1H), 7.59(t, 1H), 7.10-7.20 (m, 4H), 6.58 (t, 1H), 3.40 (m, 2H), 2.75 (t, 2H),2.28 (s, 3H); Anal. Calcd for C₁₉H₁₉N₃O.0.2 H₂O: C, 73.86; H, 6.33; N,13.60. Found: C, 73.69; H, 6.53; N, 13.51.

EXAMPLE 40 N-[2-(2,4-dimethylphenyl)ethyl]-N′-isoquinolin-5-ylurea

The title compound was prepared using 2-(2,4-dimethylphenyl)ethylamine,the product from Example 1A, DBU and the procedure described in Example1B. MS (ESI+) m/z 320 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 9.26 (s, 1H),8.66 (bs, 1H), 8.53 (d, 1H), 8.28 (m, 1H), 7.90 (d, 1H), 7.73 (d, 1H),7.59 (t, 1H), 7.08 (d, 1H), 6.92-7.02 (m, 2H), 6.63 (t, 1H), 3.34 (m,2H), 2.75 (t, 2H), 2.29 (s, 3H), 2.24 (s, 3H); Anal. Calcd forC₂₀H₂₁N₃O.0.45 H₂O: C, 73.35; H, 6.74; N, 12.83. Found: C, 73.70; H,6.53; N, 12.45.

EXAMPLE 41 N-isoquinolin-5-yl-N′-[2-(2-methylphenyl)ethyl]urea

The title compound was prepared using 2-(2-methylphenyl)ethylamine, theproduct from Example 1A, DBU and the procedure described in Example 1B.MS (ESI−) m/z 324 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ 9.26 (s, 1H), 8.64(bs, 1H), 8.53 (d, 1H), 8.25 (m, 1H), 7.89 (d, 1H), 7.73 (d, 1H), 7.59(t, 1H), 7.46 (dd, 1H), 7.40 (dd, 1H), 7.23-7.36 (m, 2H), 6.67 (t, 1H),3.44 (m, 2H), 2.94 (t, 2H); Anal. Calcd for C₁₈H₁₆ClN₃O: C, 66.36; H,4.95; N, 12.90. Found: C, 66.19; H, 4.87; N, 12.91.

EXAMPLE 42 N-isoquinolin-5-yl-N′-{4-[(trifluoromethyl)thio]benzyl}urea

The title compound was prepared using4-[(trifluoromethyl)thio]benzylamine, the product from Example 1A, DBUand the procedure described in Example 1B. MS (ESI−) m/z 376 (M−H)⁻; ¹HNMR (300 MHz, DMSO-d₆) δ 9.27 (s, 1H), 8.82 (bs, 1H), 8.54 (d, 1H), 8.27(dd, 1H), 7.95 (d, 1H), 7.68-7.78 (m, 3H), 7.60 (t, 1H), 7.51 (d, 2H),7.17 (t, 1H), 4.45 (d, 2H); Anal. Calcd for C₁₈H₁₄F₃N₃OS: C, 57.29; H,3.74; N, 11.13. Found: C, 57.00; H, 3.73; N, 11.04.

EXAMPLE 42 N-isoquinolin-5-yl-N′-[3-(trifluoromethyl)benzyl]urea

The title compound was prepared using 3-(trifluoromethyl)benzylamine,the product from Example 1A, DBU and the procedure described in Example1B. MS (ESI−) m/z 344 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ 9.27 (s, 1H),8.82 (bs, 1H), 8.53 (d, 1H), 8.25 (dd, 1H), 7.94 (d, 1H), 7.55-7.79 (m,6H), 7.18 (t, 1H), 4.47 (d, 2H); Anal. Calcd for C₁₈H₁₄F₃N₃O: C, 62.61;H, 4.09; N, 12.17. Found: C, 62.39; H, 3.87; N, 12.28.

EXAMPLE 43 N-isoquinolin-5-yl-N′-(4-methoxybenzyl)urea

The title compound was prepared using 4-methoxybenzylamine, the productfrom Example 1A, DBU and the procedure described in Example 1B. MS(ESI−) m/z 306 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ 9.26 (s, 1H), 8.70(bs, 1H), 8.53 (d, 1H), 8.31 (dd, 1H), 7.92 (d, 1H), 7.73 (d, 1H), 7.60(t, 1H), 7.29 (m, 2H), 6.88-7.03 (m, 3H), 4.30 (d, 2H), 3.74 (s, 3H);Anal. Calcd for C₁₈H₁₇N₃O₂: C, 70.34; H, 5.58; N, 13.67. Found: C,70.21; H, 5.47; N, 13.46.

EXAMPLE 44N-[4-chloro-3-(trifluoromethyl)benzyl]-N′-isoquinolin-5-ylurea

The title compound was prepared using4-chloro-3-(trifluoromethyl)benzylamine, the product from Example 1A,DBU and the procedure described in Example 1B. MS (ESI−) m/z 378 (M−H)⁻;¹H NMR (300 MHz, DMSO-d₆) δ 9.73 (s, 1H), 9.53 (s, 1H), 8.69 (d, 1H),8.61 (d, 1H), 8.54 (d, 1H), 8.07 (d, 1H), 7.82-7.92 (m, 2H), 7.63-7.75(m, 3H), 4.47 (d, 2H); Anal. Calcd for C₁₈H₁₃ClF₃N₃O.1.2 HCl: C, 51.05;H, 3.38; N, 9.92. Found: C, 51.26; H, 3.68; N, 9.50.

EXAMPLE 45 N-(3,5-dimethylbenzyl)-N′-isoquinolin-5-ylurea

The title compound was prepared using 3,4-dimethylbenzylamine, theproduct from Example 1A, DBU and the procedure described in Example 1B.MS (ESI−) m/z 304 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ 9.74 (s, 1H), 9.41(bs, 1H), 8.69 (d, 1H), 8.62 (d, 2H), 8.05 (d, 1H), 7.88 (t, 1H), 7.44(t, 1H), 6.96 (bs, 2H), 6.89 (bs, 1H), 4.31 (d, 2H), 2.26 (s, 6H); Anal.Calcd for C₁₉H₁₉N₃O.1.1 HCl: C, 66.05; H, 5.86; N, 12.16. Found: C,66.09; H, 5.83; N, 12.14.

EXAMPLE 46 N-(3,5-difluorobenzyl)-N′-isoquinolin-5-ylurea

The title compound was prepared using 3,5-difluorobenzylamine, theproduct from Example 1A, DBU and the procedure described in Example 1B.MS (ESI−) m/z 312 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ 9.76 (s, 1H), 9.66(bs, 1H), 8.65-8.79 (m, 2H), 8.60 (d, 1H), 8.08 (d, 1H), 7.89 (t, 1H),7.77 (t, 1H), 7.02-7.18 (m, 3H), 4.43 (d, 2H); Anal. Calcd forC₁₇H₁₃F₂N₃O.HCl.0.3 H₂O: C, 57.49; H, 4.14; N, 11.83. Found: C, 57.76;H, 4.59; N, 11.76.

EXAMPLE 47 N-hexyl-N′-isoquinolin-5-ylurea

The title compound was prepared using hexylamine, the product fromExample 1A, DBU and the procedure described in Example 1B. MS (ESI−) m/z270 (M−H)⁻; ¹H NMR (DMSO-d₆) δ 9.25 (s, 1H), 8.60 (s, 1H), 8.55 (d, 1H),8.39 (d, 1H), 7.93 (d, 1H), 7.71 (d, 1H), 7.59 (t, 1H), 6.60 (t, 1H),3.15 (q, 2H), 1.49 (m, 2H), 1.32 (m, 6H), 0.90 (m, 3H).

EXAMPLE 48 N-(4-bromobenzyl)-N′-isoquinolin-5-ylurea

The title compound was prepared using 4-bromobenzylamine, the productfrom Example 1A, DBU and the procedure described in Example 1B. MS(ESI−) m/z 355 (M−H)⁻; ¹H NMR (DMSO-d₆) δ 9.27 (s, 1H), 8.78 (s, 1H),8.53 (d, 1H), 8.27 (d, 1H), 7.93 (d, 1H), 7.74 (d, 1H), 7.61 (d, 1H),7.55 (d, 2H), 7.42 (d, 2H) 7.10 (t, 1H); Anal. Calcd for C₁₇H₁₄BrN₃O: C,57.32; H, 3.96; N, 11.80. Found C, 57.05; H, 3.79; N, 11.64.

EXAMPLE 49 N-(3,5-dimethoxybenzyl)-N′-isoquinolin-5-ylurea

The title compound was prepared using 3,5-dimethoxybenzylamine, theproduct from Example 1A, DBU and the procedure described in Example 1B.MS (ESI−) m/z 336 (M−H)⁻; ¹H NMR (DMSO-d₆) δ 9.70 (s, 1H), 9.32 (s, 1H),8.69 (d, 1H), 8.55 (dd, 2H), 8.10 (d, 1H), 7.85 (t, 1H), 7.39 (t, 1H),6.54 (s, 2H), 6.41 (s, 1H) 4.35 (d, 2H), 3.75 (s, 6H); Anal. Calcd forC₁₉H₁₉N₃O₃ 1.25 HCl C, 59.59; H, 5.33; N, 10.97. Found C, 59.22; H,5.41; N, 10.84

EXAMPLE 50 N-isoquinolin-5-yl-N′-(3,4,5-trimethoxybenzyl)urea

The title compound was prepared using 3,4,5-trimethoxybenzylamine, theproduct from Example 1A, DBU and the procedure described in Example 1B.MS(ESI−) m/z 366 (M−H)⁻; ¹H NMR (DMSO-d₆) δ 9.79 (s, 1H), 9.50 (s, 1H),8.69 (d, 1H), 8.80 (d, 1H), 8.65 (dd, 2H), 8.08 (d, 1H), 7.90 (d, 1H),7.68 (m, 1H), 6.71 (s, 2H), 4.53 (d, 2H) 3.79 (s, 6H), 3.53 (s, 3H).Anal. Calcd for C₂₀H₂₁N₃O₄ 1.3 HCl: C, 57.91; H, 5.42; N, 10.13. FoundC, 57.65; H, 5.60; N, 10.09.

EXAMPLE 51 N-isoquinolin-5-yl-N′-[4-(methylsulfonyl)benzyl]urea

The title compound was prepared using 4-(methylsulfonyl)benzylamine, theproduct from Example 1A, DBU and the procedure described in Example 1B.MS (ESI−) m/z 354 (M−H)⁻; ¹H NMR (DMSO-d₆) δ 9.65 (s, 1H), 9.30 (s, 1H),8.65 (d, 1H), 8.49 (d, 1H), 8.42 (d, 1H), 8.00 (d, 1H), 7.91 (d, 2H),7.82 (t, 1H), 7.61 (d, 2H), 7.47 (t, 1H), 4.50 (d, 2H), 3.20 (s, 3H);Anal. Calcd for C₂₀H₂₁N₃O₄ 1.0 HCl: C, 55.17; H, 4.63; N, 10.72. FoundC, 54.92; H, 4.54; N, 10.42.

EXAMPLE 52 N-(3,4-dimethoxybenzyl)-N′-isoquinolin-5-ylurea

The title compound was prepared using 3,4-dimethoxybenzylamine, theproduct from Example 1A, DBU and the procedure described in Example 1B.MS (ESI−) m/z (M−H)⁻336; ¹H NMR (DMSO-d₆) δ 9.78 (s, 1H), 9.50 (s, 1H),8.70 (s, 2H), 8.62 (d, 1H), 8.05 (d, 1H), 7.87 (t, 1H), 7.51 (t, 1H),6.99 (s, 1H), 6.79 (ds, 2H), 4.32 (d, 2H), 3.75 (s, 3H), 3.71 (s. 3H);Anal. Calcd for C₁₉H₁₉N₃O₃ 1.0 HCl: C, 61.04; H, 5.39; N, 11.24. FoundC, 60.82; H, 5.38; N, 11.19.

EXAMPLE 53 N-isoquinolin-5-yl-N′-(3-phenoxybenzyl)urea

The title compound was prepared using 3,4-dimethoxybenzylamine, theproduct from Example 1A, DBU and the procedure described in Example 1B.MS (ESI−) m/z 368 (M−H)⁻; ¹H NMR (DMSO-d₆) δ 9.65 (s, 1H), 9.25 (s, 1H),8.65 (d, 1H), 8.52 (d, 1H), 8.48 (d, 1H), 8.03 (d, 1H), 7.82 (t, 1H),7.35 (m, 4H), 7.15 (d, 2H), 7.05 (s, 2H), 7.00 (s, 1H), 6.84 (d, 1H),2.37 (d, 2H); Anal. Calcd for C₂₃H₁₉N₃O₂ 1.25 HCl: C, 66.57; H, 4.92; N,10.13. Found C, 66.49; H, 5.02; N, 10.14.

EXAMPLE 54 N-isoquinolin-5-yl-N′-(1-naphthylmethyl)urea

The title compound was prepared using 1-naphthylmethylamine, the productfrom Example 1A, DBU and the procedure described in Example 1B. MS(ESI+) m/z 328 (M+H)⁺; HRMS (FAB): Calculated for C₂₁H₁₈N₃O 328.1450;observed 328.1438 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 9.25 (s, 1H), 8.48, (d,1H), 8.39 (d, 1H), 8.22 (d, 1H), 8.19 (d, 1H), 7.97 (d, 1H), 7.87 (d,1H), 7.78-7.71 (m, 2H), 7.63-7.49 (m, 6H), 4.85 (d, 2H).

EXAMPLE 55 N-(2,4-dimethylbenzyl)-N′-isoquinolin-5-ylurea

The title compound was prepared using 2,4-dimethylbenzylamine, theproduct from Example 1A, DBU and the procedure described in Example 1B.MS (ESI+) m/z 306 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 9.26 (s, 1H), 8.67 (s, 1H),8.53 (d, 1H), 8.32 (d, 1H), 7.92 (d, 1H), 7.72 (d, 1H), 7.60 (t, 1H),7.19 (d, 1H), 7.03-6.95 (m, 2H), 9.90 (t, 1H), 4.31 (d, 2H), 2.30 (s,3H), 2.26 (s, 3H); Anal. Calcd for C₁₉H₁₉N₃O.0.2H₂O: C, 73.86, H 6.33,N, 13.60. Found: C, 73.75, H, 6.49, N, 13.49.

EXAMPLE 56 N-[4-(dimethylamino)benzyl]-N′-isoquinolin-5-ylurea

The title compound was prepared using4-(aminomethyl)-N,N-dimethylaniline, the product from Example 1A, DBUand the procedure described in Example 1B. MS (ESI+) m/z 321 (M+H)⁺; ¹HNMR (DMSO-d₆) δ 9.26 (s, 1H), 8.71 (s, 1H), 8.52 (d, 1H), 8.32 (d, 1H),7.93 (d, 1H), 7.72 (d, 1H), 7.59 (t, 1H), 7.18 (d, 2H), 6.96 (t, 1H),6.71 (d, 2H), 4.23 (d, 2H), 2.86 (s, 6H); Anal. Calcd forC₁₉H₂₀N₄O.0.7H₂O: C, 68.53, H 6.48, N 16.82. Found: C 68.59, H, 6.48, N,16.60.

EXAMPLE 57 N-isoquinolin-8-yl-N′-[4-(trifluoromethyl)benzyl]urea EXAMPLE57A 5-bromoisoquinoline

Concentrated H₂SO₄ (260 mL) was cooled to −25° C. while stirring with amechanical stirrer. Isoquinoline (30 mL, 0.25 mol) was added slowly sothe temperature did not exceed 0° C. After the addition was complete thered solution was recooled to −25° C. and treated with N-bromosuccinimide(55.49 g, 0.31 mol) in small portions so that the temperature did notexceed −20° C. The reaction mixture was stirred for 5 hours keeping thetemperature between −30° C. and −18° C. The reaction mixture was thenallowed to warm to −10° C. and was poured carefully over 600 g of ice.The resulting slurry was adjusted to pH 10 using 25% NH₄OH. The mixturewas then extracted with diethyl ether (3×600 mL). The ether fractionswere combined, filtered through a celite plug and the filtrateconcentrated under reduced pressure. The residue was suspended in hotheptane (600 mL). The heptane was decanted. This procedure was repeatedwith hexane (2×200 mL). The combined heptane and hexane fractions wereconcentrated under reduced pressure to give a mustard yellow solid. Thetitle compound was obtained by recrystallization from heptane (26.37 g,50%). mp 78°-80° C.; MS (ESI+) m/z 209 (M+H)⁺; ¹H NMR (DMSO, 300 MHz) δ7.65 (t, J 7.9, 1H), 7.94 (d, J 8.1, 1H), 8.17 (dd, J 1.0, 7.4, 1H),8.22 (d, J 8.1, 1H), 8.68 (d, J 6.1, 1H), 9.37 (s, 1H); Anal. Calcd forC₉H₆BrN: C, 51.96; H, 2.91; N, 6.73; Br, 38.41. Found: C, 51.24; H,2.79; N, 6.52; Br, 38.81.

EXAMPLE 57B 5-bromo-8-nitroisoquinoline

The diethyl ether solution from Example 57A was treated with potassiumnitrate (10.1 g, 100 mmol). After stirring for one hour, The mixture waspoured onto ice and neutralized with concentrated ammonium hydroxide(˜300 ml). The crude product was collected by filtration, dried, andrecrystalization from methanol to provide the title compound (8.83 g).

EXAMPLE 57C isoquinolin-8-amine

The product from Example 57B was treated with Pd/C under a hydrogenatmosphere to provide the title compound.

EXAMPLE 57D 2,2,2-trichloro-N-isoquinolin-8-ylacetamide

The product from Example 57C and trichloroacetylchloride were processedas described in Example 1A to provide the title compound.

EXAMPLE 57E N-isoquinolin-8-yl-N′-[4-(trifluoromethyl)benzyl]urea

The title compound was prepared using 4-(trifluoromethyl)benzylamine,the product from Example 57D, DBU and the procedure described in Example1B. MS (ESI+) m/z 346 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 9.58 (s, 1H), 9.10 (s,1H), 8.49 (d, 1H), 8.12 (d, 1H), 7.81-7.54 (m, 7H), 7.20 (t, 1H), 4.47(d, 2H); Anal. Calcd for C₁₈H₁₄F₃N₃O.0.2 H₂O: C, 61.96, H 4.16, N 12.04.Found: C, 62.06, H 4.23, N 11.91.

EXAMPLE 58 N-(4-bromobenzyl)-N′-isoquinolin-8-ylurea

The title compound was prepared using 4-bromobenzylamine, the productfrom Example 57D, DBU and the procedure described in Example 1B. MS(ESI+) m/z 356 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 9.52 (s, 1H), 9.15 (s, 1H),8.49 (d, 1H), 8.11 (d, 1H), 7.77 (d, 1H), 7.67 (t, 1H), 7.55 (m, 3H)7.32 (d, 2H), 7.25 (t, 1H), 4.34 (d, 2H); Anal. Calcd forC₁₇H₁₄BrN₃O.0.25 H₂O.0.16 MeOH: C, 56.34, H, 4.17, N, 11.49. Found C,56.32, H 4.45, N 11.70.

EXAMPLE 60 N-(4-bromobenzyl)-N′-(3-chloroisoquinolin-5-yl)urea EXAMPLE60A isoquinoline-1,3(2H,4H)-dione

2-(Carboxymethyl)benzoic acid (10 g, 55.6 mmol) was dissolved inconcentrated NH₄OH (15 mL) and then was evaporated to dryness underreduced pressure. The process was repeated with additional NH₄OH (5 mL).The resulting residue was treated with 1,2-dichlorobenzene (20 mL) andheated with stirring at 200° C. without a condenser allowing the solventto evaporate. The concentrated mixture was allowed to cool to roomtemperature, diluted with methanol (20 mL), and allowed to standovernight. The precipitate was collected by filtration, washed withmethanol, and dried under reduced pressure to provide the title compoundas tan needles (6.6 g, 74%).

EXAMPLE 60B 1,3-dichloroisoquinoline

The product from Example 60A (6.5 g, 40.4 mmol) was treated withphenylphosphonic dichloride (11.5 mL, 81.1 mmol) and heated at 160° C.for 3 hours. The reaction was allowed to cool to room temperature andstand overnight. The resulting waxy orange material was dissolved intetrahydrofuran (200 mL), treated with water (60 mL), and thenconcentrated under reduced to remove the tetrahydrofuran. The remainingaqueous material was neutralized with concentrated NH₄OH and extractedwith ethyl acetate. The ethyl acetate phases were combined, washed withwater, brine, dried over Na₂SO₄ and concentrated under reduced pressureto provide the title compound as yellow flakes(6.92 g, 74%).

EXAMPLE 60C 3-chloroisoquinoline

The product from Example 60B (6.73 g, 33.8 mmol) was suspended inglacial acetic acid (37 mL) and concentrated HCl (13 mL), treated withtin powder (12.1 g, 101.9 mmol), and heated at 55-60° C. for 3 hourswith stirring. The mixture was allowed to cool to room temperature andthe precipitated tin salts were removed by filtration through Celite.The filtrate was basified to pH 9 with concentrated NH₄OH and thenextracted with ethyl aceate. The organic extracts were combined, washedwith saturated NaHCO₃ solution, dried over Na₂SO₄, and concentratedunder reduced pressure to provide the title compound as a gummy yellowresidue (1.28 g, 23%).

EXAMPLE 60D 3-chloro-5-nitroisoquinoline

The product from Example 60C (1.28 g, 7.85 mmol) in concentrated H₂SO₄.(30 mL) at 0° C. was treated with a solution of KNO₃ (0.84 g, 8.32 mmol)in concentrated H₂SO₄ (5 mL) dropwise over 5 minutes. The mixture wasstirred at 0° C. for 10 minutes, allowed to warm to room temperature,and stirred overnight. The mixture was poured onto 65 g of ice and theprecipitated yellow solid was collected by filtration. The solid wasslurried in water, collected by filtration, washed with water, andallowed to air-dry to provide the title compound as a pale yellow solid(0.45 g, 28%).

EXAMPLE 60E 3-chloroisoquinolin-5-amine

The product from Example 60D (0.45 g, 2.16 mmol) was suspended inglacial acetic acid (4 mL) and warmed to 60° C. while adding water (4mL). The heated mixture was treated with powdered iron (0.33 g, 5.91mmol) in three portions over about 2 minutes. The reaction mixturestirred at 60° C. for 2 hours, allowed to cool to room temperature andstir overnight. The mixture was basified with 25% aqueous NaOH, dilutedwith a little water, and the brown precipitate was collected byfiltration and dried overnight at 50° C. in a vacuum oven. The filtercake was then broken up and extracted with boiling ethyl acetate. Theextracts were combined, dried over Na₂SO₄, filtered, and the filtratewas concentrated under reduced pressure to provide the title compound asa gold-orange solid (200 mg, 52%).

EXAMPLE 60F N-(4-bromobenzyl)-N′-(3-chloroisoquinolin-5-yl)urea

The product from Example 60E (250 mg, 1.4 mmol) and1-bromo-4-(isocyanatomethyl)benzene (0.22 mL, 1.57 mmol) were heated intoluene (5 mL) at 80° C. for 3 hours. The mixture was allowed to cool toroom temperature, filtered, the filter cake was washed with toluene, andair-dried to provide the title compound (335 mg, 61%). ¹H NMR (300 MHz,DMSO-d₆) δ 9.18 (s, 1H), 8.81 (s, 1H), 8.32 (dd, J=7.8 Hz, 0.7 Hz, 1H),8.09 (s, 1H), 7.80 (d, J=8.2 Hz, 1H), 7.53-7.65 (m, 3H), 7.32 (m, 2H),7.05 (t, J=5.7 Hz, 1H), 4.35 (d, J=5.7 Hz, 2H); MS (ESI⁺) m/z 391/393(M+H⁺, ³⁵Cl/³⁷Cl).

EXAMPLE 61 4-cyanobenzyl isoquinolin-5-ylcarbamate EXAMPLE 61A5-isocyanatoisoquinoline

Phosgene (20 ml, 20% in toluene from Fluka) in CH₂Cl₂ (300 mL) at 0° C.was treated with DMAP (10 g) in CH₂Cl₂ (100 mL) slowly. After completeaddition, the mixture was treated with 5-aminoisoquinoline (5 g) inCH₂Cl₂ (100 mL) dropwise. The mixture was allowed to warm to roomtemperature and then stirred overnight. The solvent was removed underreduced pressure. The solid residue was extracted with diethyl ether(400 mL). The diethyl ether was filtered to provide the title compoundin diethyl ether as a pale yellow solution. The diethyl ether solutionwas used in subsequent reactions without further purification.

EXAMPLE 61B 4-cyanobenzyl isoquinolin-5-ylcarbamate

4-Cyanobenzyl alcohol (150 mg, 1.13 mmol) in diethyl ether (10 mL) wastreated with the product from Example 61A as an ethereal solution. Themixture was stirred for 2 hours, filtered, and the filter cake waswashed with diethyl ether to provide the title compound as an off-whitesolid (150 mg, 44%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.95 (s, 1H), 9.32 (d,J=1.0 Hz, 1H), 8.52 (d, J=6.1 Hz, 1H), 7.88-7.99 (m, 5H), 7.65-7.70 (m,3H), 5.31 (s, 2H); MS (ESI⁺) m/z 304 (M+H)⁺.

EXAMPLE 62 N-[(4-cyanophenyl)methyl]-N′-isoquinolin-5-ylurea

N,N-bis(tert-butoxycarbonyl)-4-cyanobenzyl amine (0.75 g, 2.25 mmol,prepared according to Synth. Comm. (1998) 28, 4419) in CH₂Cl₂ (15 mL)was treated with trifluoroacetic acid (8 mL), and the resulting mixturewas stirred at room temperature for 3 hours. The mixture wasconcentrated under reduced pressure and then azeotroped with diethylether. The residue was taken up in diethyl ether (10 mL) and treatedwith N,N-diisopropylethylamine (5 mL) and the product from Example 61A.After stirring for 1 hour, the mixture was filtered and the filter waspurified by chromatography (95:5 CH₂Cl₂-MeOH) to provide the titlecompound as a white solid (65 mg). The corresponding hydrochloride saltwas prepared using methanolic HCl. ¹H NMR (300 MHz, DMSO-d₆) δ 9.75 (s,1H), 9.62 (s, 1H), 8.69 (s, 2H), 8.58 (dd, J=7.8 Hz, 1.0 Hz, 1H), 8.07(d, J=7.4 Hz, 1H), 7.90 (d, J=8.1 Hz, 1H), 7.81-7.85 (m, 2H), 7.74 (t,J=6.1 Hz, 1H), 7.54-7.57 (m, 2H), 4.48 (d, J=6.1 Hz, 2H); MS (ESI⁺) m/z303 (M+H)⁺.

EXAMPLE 63 N-[(4-bromophenyl)methyl]-N′-(3-methylisoquinolin-5-yl)ureaEXAMPLE 63A 3-methylisoquinolin-5-amine

3-Methylisoquinoline was processed as described in Examples 60D and 60Eto provide the title compound.

EXAMPLE 63B N-[(4-bromophenyl)methyl]-N′-(3-methylisoquinolin-5-yl)urea

The product from Example 63A (500 mg, 3.1 mmol) in toluene (10 mL) wastreated with 1-bromo-4-(isocyanatomethyl)benzene (0.5 mL, 3.57 mmol)with stirring and then the mixture was heated at 80° C. overnight. Themixture was allowed to cool to room temperature, filtered, the filtercake was washed with toluene, and allowed to air-dry to provide thetitle compound. The corresponding hydrochloride salt was prepared usingmethanolic HCl to afford a tan solid (919 mg, 73%). ¹H NMR (300 MHz,DMSO-d₆) δ 9.70 (s, 1H), 9.54 (s, 1H), 8.63 (s, 1H), 8.57 (dd, J=7.8 Hz,1.0 Hz, 1H), 8.02 (d, J=8.2 Hz, 1H), 7.78-7.83 (m, 1H), 7.67-7.71 (m,1H), 7.52-7.57 (m, 2H), 7.30-7.35 (m, 2H), 4.36 (d, J=5.7 Hz, 2H), 2.78(s, 3H); MS (ESI⁺) m/z 370/372 (M+H, ⁷⁹Br/⁸¹Br).

EXAMPLE 64 N-[(4-bromophenyl)methyl]-N′-(1-chloroisoquinolin-5-yl)ureaEXAMPLE 64A 1-chloroisoquinolin-5-amine

1-Chloroisoquinoline was processed as described in Examples 60D and 60Eto provide the title compound.

EXAMPLE 64B N-[(4-bromophenyl)methyl]-N′-(1-chloroisoquinolin-5-yl)urea

The product from Example 64A (520 mg, 2.91 mmol) in toluene (8 mL) wastreated with 1-bromo-4-(isocyanatomethyl)benzene (0.41 mL, 2.93 mmol)with stirring and then the mixture was heated at 90° C. for 2 hours. Themixture was allowed to cool to room temperature, filtered, the filtercake washed with toluene, and air-dried to provide the title compound asan off-white solid (717 mg, 63%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.89 (s,1H), 8.34-8.37 (m, 2H), 8.00 (dd, J=6.1 Hz, 0.7 Hz, 1H), 7.92-7.95 (m,1H), 7.73 (t, J=8.1, 1H), 7.53-7.56 (m, 2H), 7.30-7.33 (m, 2H), 7.12 (t,J=5.8Hz, 1H), 4.35 (d, J=5.8 Hz, 2H); MS (ESI⁺) m/z 390/392 (M+H⁺,³⁵Cl/³⁷Cl).

EXAMPLE 65 N-[(4-bromophenyl)methyl]-N′-(1-methylisoquinolin-5-yl)ureaEXAMPLE 65A 1-methylisoquinolin-5-amine

1-Methylisoquinoline was processed as described in Examples 60D and 60Eto provide the title compound.

EXAMPLE 65B N-[(4-bromophenyl)methyl]-N′-(1-methylisoquinolin-5-yl)urea

The product from Example 65A (480 mg, 3.04 mmol) in toluene (9 mL) wastreated with 1-bromo-4-(isocyanatomethyl)benzene (0.43, 3.07 mmol) withstirring. After heating the mixture at 90° C. for 1 hour, the mixturewas allowed to cool to room temperature, filtered, and the filter cakewashed with toluene to provide the title compound. The correspondingdi-hydrochloride salt was prepared using methanolic HCl (680 mg, 50%).¹H NMR (300 MHz, DMSO-d₆) δ 8.74 (s, 1H), 8.38 (d, J=6.1 Hz, 1H), 8.25(d, J=7.8 Hz, 1H), 7.78-7.85 (m, 2H), 7.53-7.61 (m, 3H), 7.32 (d, J=8.5Hz, 2H), 7.11 (t, J=6.1 Hz, 1H), 4.34 (d, J=6.1 Hz, 2H), 2.88 (s, 3H);MS (ESI⁺) m/z 370/372 (M+H⁺, ⁷⁹Br/⁸¹Br).

EXAMPLE 66 N-isoquinolin-5-yl-N′-[(4-morpholin-4-ylphenyl)methyl]ureaEXAMPLE 66A 4-morpholin-4-ylbenzonitrile

4-Fluorobenzonitrile (1 g, 8.26 mmol) and morpholine (2.2 mL, 25.2 mmol)were combined in DMSO (25 mL) and heated at 100° C. for 2.5 hours. Themixture was allowed to cool to room temperature, poured into water, andextracted with diethyl ether. The organic extracts were combined, washedwith water and brine, dried over Na₂SO₄, and concentrated under reducedpressure to provide the title compound as a white solid (1.24 g, 80%).

EXAMPLE 66B (4-morpholin-4-ylphenyl)methylamine

The product from Example 66A (1.24 g, 6.6 mmol) in THF (25 mL) wastreated with LiAlH₄ (2.5 g, 65.9 mmol) at 0° C. The mixture was allowedto warm to room temperature and then refluxed for 1 hour. The mixturewas allowed to cool to room temperature and then treated with 1N NaOHcarefully followed by water. The mixture was concentrated under reducedpressure and the resulting aqueous mixture was extracted with diethylether. The organic extracts were combined, washed with saturated NaHCO₃solution, dried over Na₂SO₄, filtered, and the filtrate concentratedunder reduced pressure to provide the title compound as a yellow oil(286 mg, 23%).

EXAMPLE 66C N-isoquinolin-5-yl-N′-[(4-morpholin-4-ylphenyl)methyl]urea

The product from Example 66B (285 mg, 1.48 mmol) in diethyl ether (10mL) was treated with the product from Example 61A. The mixture wasfiltered and the filter cake purified by chromatography (95:5CH₂Cl₂-MeOH, eluant) to provide that title compound as a white solid.The corresponding di-hydrochloride salt was prepared using methanolicHCl to afford a yellow solid (505 mg, 78%). ¹H NMR (300 MHz, DMSO-d₆)δ9.26 (s, 1H), 8.67 (s, 1H), 8.52-8.55 (m, 1H), 8.32 (dd, J=7.8 Hz, 1.1Hz, 1H), 7.92 (d, J=6.1 Hz, 1H), 7.73 (d, J=8.2 Hz, 1H), 7.60 (m, 1H),7.23 (d, J=8.8 Hz, 2H), 6.92-6.96 (m, 3H), 4.26 (d, 5.4 Hz, 2H),3.72-3.75 (m, 4H), 3.06-3.12 (m, 4H); MS (ESI⁺) m/z 363 (M+H)⁺.

EXAMPLE 67N-{[4-(2,6-dimethylmorpholin-4-yl)phenyl]methyl}-N′-isoquinolin-5-ylureaEXAMPLE 67A [4-(2,6-dimethylmorpholin-4-yl)phenyl]methylamine

4-Fluorobenzonitrile and 2,6-dimethylmorpholine were processed asdescribed in Examples 66A and 66B to provide the title compound.

EXAMPLE 67BN-{[4-(2,6-dimethylmorpholin-4-yl)phenyl]methyl}-N′-isoquinolin-5-ylurea

The product from Example 67A and the product from Example 61A wereprocessed as described in Example 66C to provide a waxy material whichwas purified by chromatography (95:5 CH₂Cl₂-MeOH, eluant) to provide thetitle compound as a white solid. The corresponding di-hydrochloride saltwas prepared using methanolic HCl. ¹H NMR (300 MHz, DMSO-d₆) δ 9.26 (s,1H), 8.67 (s, 1H), 8.53 (d, J=6.1 Hz, 1H), 8.31 (dd, J=7.6 Hz, 1.1 Hz,1H), 7.92 (d, J=6.1 Hz, 1H), 7.73 (d, J=8.1 Hz, 1H), 7.57-7.62 (m, 1H),7.22 (d, J=8.8 Hz, 2H), 6.92-6.95 (m, 3H), 4.26 (d, J=5.7 Hz, 2H), 3.68(m, 2H), 3.54-3.57 (m, 2H), 2.21 (m, 2H), 1.16 (s, 3H), 1.14 (s, 3H); MS(ESI⁺) m/z 391 (M+H).

EXAMPLE 68N-isoquinolin-5-yl-N′-[(4-thiomorpholin-4-ylphenyl)methyl]urea EXAMPLE68A (4-thiomorpholin-4-ylphenyl)methylamine

4-Fluorobenzonitrile and thiomorpholine were processed as described inExamples 66A and 66B to provide the title compound.

EXAMPLE 68BN-isoquinolin-5-yl-N′-[(4-thiomorpholin-4-ylphenyl)methyl]urea

The product from Example 68A and the product from Example 61A wereprocessed as described in Example 66C to provide the title compound. Thefree base was treated with methanolic HCl to form the correspondingdi-hydrochloride salt. ¹H NMR (300 MHz, DMSO-d₆) δ 9.26 (s, 1H), 8.67(s, 1H), 8.53 (d, J=6.1 Hz, 1H), 8.32 (dd, J=7.8 Hz, 1.1 Hz, 1H), 7.92(d, J=6.1 Hz, 1H), 7.73 (d, J=8.2 Hz, 1H), 7.60 (m, 1H), 7.20-7.23 (m,2H), 6.90-6.96 (m, 3H), 4.25 (d, J=5.8 Hz, 2H), 3.45-3.51 (m, 4H),2.64-2.67 (m, 4H); MS (ESI⁺) m/z 379 (M+H)⁺.

EXAMPLE 694-(3,4-dichlorophenyl)-N-isoquinolin-5-ylpiperazine-1-carboxamide

1-(3,4-Dichlorophenyl)piperazine (1280 mg, 5.55 mmol) in diethyl ether(30 mL) was treated with the product from Example 61A (˜40 mL). Themixture was filtered, the filter cake washed with diethyl ether, anddried under reduced pressure to provide the title compound as a whitesolid (1.78 g, 80%). ¹H NMR (300 MHz, DMSO-d₆) δ 9.29 (d, J=1.0 Hz, 1H),8.84 (s, 1H), 8.49 (d, J=5.8 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.78 (m,1H), 7.61-7.71 (m, 2H), 7.44 (d, J=8.8 Hz, 1H), 7.22 (d, J=3.1 Hz, 1H),7.01 (dd, J=9.1, 2.7 Hz, 1H), 3.68 (m, 4H), 3.30 (m, 4H); MS (ESI⁺) m/z401/403 (M+H⁺, ³⁵Cl/³⁷Cl).

EXAMPLE 70 2-isoquinolin-5-yl-N-[4-(trifluoromethyl)benzyl]acetamideEXAMPLE 70A ethyl isoquinolin-5-yl(oxo)acetate

The product from Example 57A (11.80 g, 56.6 mmol) in THF (200 mL) at−78° C. was treated with n-butyllithium (30 mL, 75.0 mmol, 2.5M inhexanes) dropwise. After 30 minutes, the mixture was treated withdiethyl oxalate (25.0 mL, 184 mmol). After 20 minutes, the solution wasallowed to warm to room temperature and was treated with saturated NH₄Cl(150 mL). The mixture was conentrated under reduced pressure. Theresidue was treated with dichloromethane (100 mL) filtered, and thefiltrate concentrated under reduced pressure. The residue was purifiedby column chromatography (20% ethyl acetate/hexanes) to provide thetitle compound as light brown oil (4.57 g, 35%). MS (ESI⁺) m/z 248(100), 230 (M+H)⁺, (ESI⁻) m/z 200 (M-Et)⁻; ¹H NMR (DMSO-d₆, 300 MHz)rotomers δ 1.26 (t, J 7.1, 0.6H), 1.37 (t, J 7.1, 2.4H), 4.21 (q, J 7.1,0.4H), 4.47 (q, J 7.1, 1.6H), 7.89 (t, J 7.5, 1H), 8.41 (dd, J 1.0, 7.5,1H), 8.57 (d, J 8.1, 1H), 8.64 (d, J 5.7, 1H), 8.73 (d, J 6.3, 1H), 9.50(s, 1H).

EXAMPLE 70B ethyl hydroxy(isoquinolin-5-yl)acetate

The product of Example 70A (1.11 g, 4.83 mmol) in absolute ethanol (20mL) was added to 10% Pd/C (115.5 mg) under an argon atmosphere. Thereaction mixture was stirred under H₂ (50 psi) for 5 hours at which timean additional 105.9 mg of catalyst was added as a suspension in ethanol.After 3 additional hours, the reaction mixture was filtered though anylon membrane and the filtrate concentrated under reduced pressure toprovide the title compound as dark brown oil (1.02 g, 91%). MS (ESI+)m/z 232 (M+H)⁺, (ESI−) m/z 202 (M-Et)⁻; ¹H NMR (DMSO-d₆, 300 MHz) δ 1.05(t, J 7.1, 3H), 4.07 (m, 2H), 5.77 (d, J 4.7, 1H), 6.36 (d, J 4.7, 1H),7.68 (dd, J 7.3, 8.1, 1H), 7.85 (d, J 7.0, 1H), 8.09 (t, J 7.5, 2H),8.53 (d, J 6.2, 1H), 9.33 (s, 1H).

EXAMPLE 70C ethyl (acetyloxy)(isoquinolin-5-yl)acetate

The product of Example 70B (1.0202 g, 4.41 mmol) in pyridine (15 mL) wastreated with acetyl chloride (0.35 mL, 4.92 mmol) dropwise. The solutionwas stirred at room temperature for 4 hours and concentrated underreduced pressure. The residue was purified by column chromatography (2%methanol/CH₂Cl₂) to provide the title compound as yellow oil (0.8100 g,67%). MS (ESI+) m/z 274 (M+H)⁺; ¹H NMR (DMSO-d₆, 300 MHz) δ 1.07 (t, J7.1, 3H), 2.17 (s, 3H), 4.13 (m, 2H), 6.62 (s, 1H), 7.74 (m, 1H), 7.94(d, J 7.1, 1H), 8.03 (d, J 6.1, 1H), 8.22 (d, J 7.6, 1H), 8.60 (d, J5.7, 1H), 9.39 (s, 1H).

EXAMPLE 70D ethyl isoquinolin-5-ylacetate

The product of Example 70C (1.43 g, 5.23 mmol) in absolute ethanol (200mL) was treated with dry 10% Pd/C (0.122 g) and triethylamine (10.4 mL).The reaction mixture was stirred at 60° C. for 6 hours under H₂ (60psi), filtered and the filtrate concentrated under reduced pressure. Theresidue was purified by column chromatography (5% methanol/CH₂Cl₂) toprovide the title compound as light brown oil (0.93 g, 67%). MS (ESI+)m/z 216 (M+H)⁺, (ESI−) m/z 214 (M−H)⁻; ¹H NMR (DMSO-d₆, 300 MHz) δ 1.17(t, J 7.1, 3H), 4.09 (q, J 7.1, 2H), 4.17 (s, 2H), 7.64 (m, 1H), 7.72(d, J 6.2, 1H), 7.81 (d, J 5.7, 1H), 8.07 (d, J 7.9, 1H), 8.54 (d, J6.1, 1H), 9.33 (s, 1H).

EXAMPLE 70E 2-isoquinolin-5-yl-N-[4-(trifluoromethyl)benzyl]acetamide

The product from Example 70D (0.207 g, 0.96 mmol) in dichloromethane (10mL) was treated with trimethylaluminum (1 mL, 2.0 mmol, 2M in toluene)dropwise. After 30 minutes, the mixture was teated with4-(trifluoromethyl)benzylamine (0.350 g, 2.0 mmol) in dichloromethane (2mL) and then refluxed for 16 hours. The reaction mixture was allowed tocool to room temperature, treated with 1M HCl (3 mL), basified tobetween pH 9 and 10 with concentrated NH₄OH, treated with water andCH₂Cl₂ and the phases separated. The organic layer was washed with water(1×10 mL), brine (1×10 mL), dried (MgSO₄), and the filtrate wasconcentrated under reduced pressure. The residue was purified by columnchromatography (5% methanol/CH₂Cl₂) to provide a yellow residue whichwas triturated with diethyl ether to provide the title compound as awhite solid (0.122 g, 37%). MS (ESI+) m/z 345 (M+H)⁺; MS (ESI−) m/z 343(M−H)⁻; ¹H NMR (DMSO, 300 MHz)δ 4.00 (s, 2H), 4.37 (d, J 5.7, 2H), 7.46(d, J 7.8, 2H), 7.67 (m, 4H), 7.93 (d, J 5.4, 1H), 8.03 (d, J 7.8, 1H),8.52 (d, J 5.8, 1H), 8.80 (t, J 5.7, 1H), 9.31 (s, 1H); Anal. Calcd forC₁₉H₁₅F₃N₂O: C, 66.28; H, 4.39; N, 8.14. Found: C, 66.16; H, 4.27; N,7.96.

EXAMPLE 71 methyl5-({[(4-bromobenzyl)amino]carbonyl}amino)isoquinoline-3-carboxylateEXAMPLE 71A methyl 5-nitroisoquinoline-3-carboxylate

Methyl isoquinoline-3-carboxylate (9.58 g, 51.2 mmol) in concentratedH₂SO₄ (100 mL) at 0° C. was treated with sodium nitrate (4.79 g, 56.4mmol) in small portions such that the temperature was maintained below5° C. Ten minutes after addition was complete, the reaction mixture wasallowed to warm to room temperature and stirred for 2 hours. The mixturewas poured over ice and adjusted to pH between 7 and 8 and filtered toafford the title compound as a bright yellow solid (11.44 g, 96%). MS(ESI+) m/z 233 (M+H)⁻; ¹H NMR (DMSO, 300 MHz) δ 3.97 (s, 3H), 8.06 (t, J8.2, 1H), 8.72 (dt, J 1.0, 8.2, 1H), 8.78 (dd, J 1.0, 7.8, 1H), 9.11 (s,1H), 9.65 (s, 1H).

EXAMPLE 71B methyl 5-aminoisoquinoline-3-carboxylate

The product of Example 71A (10.33 g, 44.5 mmol) in acetic acid/water(3/1) (320 mL) was treated with iron powder (5.06 g, 90.7 mmol). Afterstirring for 16 hours at room temperature, the reaction mixture wasfiltered the filtrate concentrated under reduced pressure toapproximately half the original volume. The mixture was then extractedwith dichloromethane (3×200 mL). The organic fractions were combined,dried (MgSO₄), and the filtrate concentrated under reduced pressure toafford crude material. A precipitate formed in the aqueous phase aftersitting for several hours. This was filtered to afford additional crudematerial. The crude material was purfidied by column chromatography (2%methanol/CH₂Cl₂) to provide the title compound. MS (ESI+) m/z 203(M+H)⁺; MS (ESI−) m/z 201 (M−H)⁻; ¹H NMR (DMSO-d₆, 300 MHz) δ 3.92 (s,3H), 6.34 (s, 2H), 6.96 (dd, J 1.0, 7.8, 1H), 7.31 (d, J 8.1, 1H), 7.51(t, J 7.9, 1H), 8.82 (s, 1H), 9.15 (s, 1H); Anal. Calcd for C₁₁H₁₀N₂O₂:C, 65.34; H, 4.99; N, 13.85. Found: C, 65.03; H, 4.95; N, 13.65.

EXAMPLE 71C methyl5-({[(4-bromobenzyl)amino]carbonyl}amino)isoquinoline-3-carboxylate

The product of Example 71B (0.156 g, 0.77 mmol) in THF:toluene (10 mL,1:1) was treated with a solution of 1-bromo-4-(isocyanatomethyl)benzene(0.201 g, 0.95 mmol) in THF (1.0 mL). After stirring for 16 hours atroom temperature, the reaction mixture was concentrated under reducedpressure and the residue was triturated with diethyl ether to providethe title compound as a tan solid (0.272 g, 85%). MS (ESI+) m/z 415(M+H)⁺; MS (ESI−) m/z 413 (M−H)⁻; ¹H NMR (DMSO-d₆, 300 MHz) δ 3.95 (s,3H), 4.36 (d, J 5.6, 2H), 7.23 (t, J 5.6, 1H), 7.33 (m, 2H), 7.56 (m,2H), 7.76 (t, J 7.8, 1H), 7.85 (d, J 8.3, 1H), 8.41 (dd, J 1.5, 7.8,1H), 8.82 (s, 1H), 9.06 (s, 1H), 9.35 (s, 1H); Anal. Calcd forC19H₆BrN₃O₃: C, 55.09; H, 3.89; N, 10.14. Found: C, 55.06; H, 3.56; N,9.84.

EXAMPLE 72 methyl5-({[(2,4-dichlorobenzyl)amino]carbonyl}amino)isoquinoline-3-carboxylate

The product of Example 71B (0.156 g, 0.77 mmol) in THF:toluene (10 mL,1:1) was treated with a solution of2,4-dichloro-1-(isocyanatomethyl)benzene (0.195 g, 0.97 mmol) in THF(1.0 mL). After stirring for 16 hours at room temperature, the reactionmixture was concentrated under reduced pressure and the residue wastriturated with diethyl ether to provide the title compound as a tansolid (0.226 g, 73%). MS (ESI+) m/z 404 (M+H)⁺; MS (ESI−) m/z 402(M−H)⁻; ¹H NMR (DMSO-d₆, 300 MHz) δ 3.96 (s, 3H), 4.44 (d, J 6.0, 2H),7.29 (m, 1H), 7.48 (m, 1H), 7.65 (d, J 1.7, 1H), 7.76 (t, J 7.8, 1H),7.86 (d, J 7.8, 1H), 8.41 (dd, J 1.0, 7.8, 1H), 8.84 (s, 1H), 9.15 (s,1H), 9.35 (s, 1H); Anal. Calcd for C₁₉H₁₅Cl₂N₃O₃: C, 56.45; H, 3.74; N,10.39. Found: C, 56.08; H, 3.67; N, 10.03.

EXAMPLE 73 N-(8-bromoisoguinolin-5-yl)-N′-(2,4-dichlorobenzyl)ureaEXAMPLE 73A 8-bromoisoquinolin-5-amine

5-Aminoisoquinoline (5.50 g, 38.1 mmol) and aluminium trichloride (15.1g, 113 mmol) were combined and heated at 80° C. in a 3-necked flaskequipped with a dropping funnel, stirrer bar, needle and sintered glasstube. Bromine (3.04 g, 19.05 mmol) was dripped onto the sintered glassfunnel and the vapour diffused onto the complex over a period of 2hours. Heating was continued for 2 hours. The suspension was addedportionwise to crushed ice and the solution basified with concentratedNaOH solution. The aqueous layer was extracted with ethyl acetate (4×100mL) and the layers were separated. The organic layers were combined,dried (Na₂SO₄), filtered and the filtrate was concentrated to give agrey solid. The grey solid was subjected to column chromatography(hexanes:ethyl acetate, 3:1) to provide the title compound (2.96 g,35%). MS (ESI+) m/z 225 (M+H)⁺; MS (ESI−) m/z 223 (M−H)⁻; ¹H NMR (CDCl₃,300 MHz) δ 4.22 (br s, 2H), 6.83 (d, J 8.1, 1H), 7.25 (s, 1H), 7.54 (d,J 5.8, 1H), 7.61 (d, J 8.1, 1H), 8.59 (d, J 5.8, 1H), 9.56 (s, 1H).

EXAMPLE 73B N-(8-bromoisoquinolin-5-yl)-N′-(2,4-dichlorobenzyl)urea

The product from Example 73A (120 mg, 0.52 mmol) in THF:toluene (1:4, 5mL) was treated with a solution of2,4-dichloro-1-(isocyanatomethyl)benzene (108 mg, 0.52 mmol) in THF (0.5mL). After stirring for 16 hours at room temperature, the mixture wasfiltered and the filter cake dried under reduced pressure to provide thetitle compound as a white solid (178 mg, 78%). The hydrochloride saltwas obtained by dissolving the product in hot THF and adding HCl indiethyl ether (2M). The yellow precipitate was collected by filtrationand dried under reduced pressure. MS (ESI+) m/z 426 (M+H)⁺; MS (ESI−)m/z 424 (M−H)⁻; ¹H NMR (DMSO-d₆, 300 MHz) δ 4.42 (d, 5.8, 2H), 7.22 (t,J 5.8, 1H), 7.65 (m, 1H), 7.91 (d, J 8.5, 1H), 8.02 (d, J 6.1, 1H), 8.22(d, J 8.5, 1H), 8.69 (d, J 5.8, 1H), 9.01 (s, 1H), 9.44 (s, 1H); Anal.Calcd for C₁₇H₁₂BrCl₂N₃O HCl 0.25 EtOH: C, 44.41; H, 3.14; N, 8.88Found: C, 44.80; H, 2.76; N, 8.84.

EXAMPLE 74 N-(8-bromoisoquinolin-5-yl)-N′-(4-fluorobenzyl)urea

The title compound was prepared using1-fluoro-4-(isocyanatomethyl)benzene, the product of Example 73A and theprocedure described in Example 73B (white solid, 108 mg, 65%). MS (ESI+)m/z 376 (M+H)⁺; MS (ESI−) m/z 374 (M−H)⁻; ¹H NMR (DMSO-d₆, 300 MHz) δ4.35 (d, 5.8, 2H), 7.12 (m, 1H), 7.18 (m, 2H), 7.40 (m, 1H), 7.91 (d, J8.5, 1H), 7.99 (d, J 6.1, 1H), 8.24 (d, J 8.5, 1H), 8.69 (d, J 5.8, 1H),8.88 (s, 1H), 9.44 (s, 1H); Anal. Calcd for C₁₇H₁₃BrFN₃O: C, 54.56; H,3.50; N, 11.23. Found: C, 54.61; H, 3.35; N, 11.14.

EXAMPLE 75 N-(8-bromoisoguinolin-5-yl)-N′-(3-fluorobenzyl)urea

The title compound was prepared using1-fluoro-3-(isocyanatomethyl)benzene, the product of Example 73A and theprocedure described in Example 73 (white solid, 108 mg, 65%). MS (ESI+)m/z 376 (M+H)⁺; MS (ESI−) m/z 374 (M−H)⁻; ¹H NMR (DMSO-d₆, 300 MHz) δ4.39 (d, 5.8, 2H), 7.09 (m, 1H), 7.17 (m, 2H), 7.40 (m, 1H), 7.91 (d, J8.5, 1H), 8.01 (d, J 6.1, 1H), 8.23 (d, J 8.5, 1H), 8.69 (d, J 5.8, 1H),8.93 (s, 1H), 9.44 (s, 1H); Anal. Calcd for C₁₇H₁₃BrFN₃O: C, 54.56; H,3.50; N, 11.23. Found: C, 54.64; H, 3.33; N, 11.19.

EXAMPLE 76 N-[1-(4-chlorophenyl)-1-methylethyl]-N′-isoquinolin-5-ylureaEXAMPLE 76A 2-(4-chlorophenyl)-2-methylpropanoyl chloride

2-(4-Chlorophenyl)-2-methylpropanoic acid (3.85 g, 19.4 mmol) in toluene(5 mL) was treated with thionyl chloride (5.00 g, 3.1 mL) and heated at80° C. for 2 hours. The cooled solution was concentrated under reducedpressure to provide a yellow oil containing a crystalline residue. Themixture was dissolved in hexane, filtered and the filtrate concentratedto provide the compound as a pale yellow oil (4.10 g, 98%).

EXAMPLE 76B 1-chloro-4-(1-isocyanato-1-methylethyl)benzene

The product of Example 76A (4.00 g, 19.4 mmol) in acetone (9 mL) at 0°C. was treated with a solution of sodium azide (1.27 g) in water (9 mL)dropwise over 15 minutes. After stirring for 30 minutes at 0° C., themixture was extracted with toluene (20 mL). The organic extract wasdried with MgSO₄, filtered, and the filtrate heated at reflux for 1hour. The mixture was allowed to cool to room temperature and wasconcentrated under reduced pressure to provide the title compound as apale yellow oil (3.45 g, 96%).

EXAMPLE 76C N-[1-(4-chlorophenyl)-1-methylethyl]-N′-isoquinolin-5-ylurea

The title compound was prepared using 5-aminoisoquinoline, the productof Example 76B and the procedure described in Example 73B except thatTHF was used as solvent. The product was recrystallized from ethylacetate to provide the title compound as a white solid (840 mg, 34%). MS(ESI+) m/z 355 (M+H)⁺; MS (ESI−) m/z 353 (M−H)⁻; ¹H NMR (DMSO-d₆, 300MHz) δ 1.63 (s, 6H), 7.23 (s, 1H), 7.37 (d, J 8.8, 2H), 7.47 (d, J 8.8,2H), 7.73 (t, J 9.2, 1H), 7.93 (d, J 8.1, 1H), 8.25 (d, J 6.4, 1H), 8.39(d, J 8.1, 1H), 8.67 (d, J 6.4, 1H), 8.87 (s, 1H), 9.58 (s, 1H); Anal.Calcd for C₁₉H₁₈ClN₃O HCl 0.25EtOH: C, 60.40; H, 5.33; N, 10.54. Found:C, 60.82; H, 5.23; N, 10.45.

EXAMPLE 77N-(4-bromobenzyl)-N′-{6-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]isoquinolin-5-yl}ureaEXAMPLE 77A2-(5-aminoisoquinolin-6-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

5-Aminoisoquinoline (288 mg, 2.00 mmol) and p-toluenesulfonic acid (5mg) were combined and treated with hexafluoroacetone hexahydrate (0.29mL, 462 mg, 2.10 mmol). The mixture was stirred in a sealed pressuretube and heated to 150° C. for 18 hours. The reaction was allowed tocool to room temperature and partitioned between CH₂Cl₂(20 mL) and water(10 mL). The organic layer was passed thru Na2SO₄ and then filteredthrough activated charcoal. The charcoal was washed with methanol (3×10mL) and the filtrate and washings were collected and concentrated underreduced pressure to provide the title compound (130 mg, 30%) as a yellowsolid. MS (ESI+) m/z 311 (M+H)⁺; MS (ESI−) m/z 309 (M−H)⁻; ¹H NMR (DMSO,300 MHz) δ 6.64 (br s, 2H), 7.30 (d, J 8.7, 1H), 7.40 (d, J 8.7, 1H),8.09 (d, J 6.1, 1H), 8.49 (d, J6.1, 1H), 9.14 (s, 1H); ¹³C NMR (DMSO,100 MHz) δ 107.02, 110.60, 113.95 (1), 115.46 (1), 122.03, 124.92,124.92, 125.94, 126.98 (1), 128.17, 142.43 (1), 144.82, 151.85 (1).

EXAMPLE 77BN-(4-bromobenzyl)-N′-{6-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]isoquinolin-5-yl}urea

The title compound was prepared using1-bromo-4-(isocyanatomethyl)benzene, the product of Example 77A and theprocedure described in Example 73B except that THF was used as solvent(white solid, 840 mg, 34%). MS (ESI+) m/z376 (M+H)⁺; MS (ESI−) m/z 374(M−H)⁻; ¹H NMR (DMSO-d₆, 300 MHz) δ 4.35 (d, 5.8, 2H), 7.12 (m, 1H),7.18 (m, 2H), 7.40 (m, 1H), 7.91 (d, J 8.5, 1H), 7.99 (d, J 6.1, 1H),8.24 (d, J 8.5, 1H), 8.69 (d, J 5.8, 1H), 8.88 (s, 1H), 9.44 (s, 1H);Anal. Calcd for C₂₀H₁₄BrF₆N₃O₂: C, 46.00; H, 3.50; N, 11.23. Found: C,54.61; H, 3.35; N, 11.14.

EXAMPLE 78 N-(4-bromobenzyl)-N′-1H-indol-4-ylurea

4-aminoindole (0.13 g, 1 mmol) in THF (3 mL) was treated with1-bromo-4-(isocyanatomethyl)benzene (0.23 g, 1.1 mmol) for 3 hours atambient temperature. Hexane was added to the reaction mixture toprecipitate 0. 26 g of the title compound as a tan solid. mp 198° C.; ¹HNMR (300 MHz, DMSO-d₆) δ 4.30 (d, 2H), 6.51 (t, 1H), 6.89 (t, 1H), 6.95(d, 2H), 7.29 (t, 1H), 7.31 (d, 2H), 7.55 (d, 2H), 7.62 (dd, 1H), 8.3(s, 1H), 11.04 (s, 1H); MS (DCI+) m/z 346 (M+H); Anal. Calcd. ForC₁₆H₁₄N₃BrO: C, 55.83; H, 4.10; N, 12.21. Found: C, 55.71, H, 4.12; N,12.01.

EXAMPLE 79 N-(3,4-dichlorobenzyl)-N′-1H-indol-4-ylurea

4-Aminoindole (0.13 g, 1 mmol) in THF (3 mL) was treated with1,2-dichloro-4-(isocyanatomethyl)benzene (0.22 g, 1.1 mmol) for 3 h atambient temperature. Hexane was added to the reaction mixture toprecipitate 0.25 g of the title compound as a tan solid. mp 201° C.; ¹HNMR (300 MHz, DMSO-d₆) δ 4.23 (d, 2H), 6.36 (s, 1H), 6.54 (t, 1H), 7.0(dd, 1H), 7.25 (m , 2H), 7.30 (d, 2H), 7.45 (d, 1H), 7.6 (m, 2H), 8.31(s, 1H), 10.87 (s, 1H) MS (DCI+) m/z 336 (M+H); Anal. Calcd. ForC₁₆H₁₃N₃Cl₂O: C, 57.50; H, 3.92; N, 12.57. Found: C, 56.94, H, 3.68; N,11.97.

EXAMPLE 80 N-1H-indol-4-yl-N′-[4-(trifluoromethyl)benzyl]urea EXAMPLE80A 4-isocyanato-1H-indole

4-Aminoindole (0.5 g, 3.78 mmol) in toluene (50 mL) was treated withtriphosgene (0.4 g, 1.35 mmol) and heated at reflux for 5 hours. Thereaction mixture was allowed to cool to room temperature andconcentrated under reduced pressure. The residue was taken up in diethylether, filtered, and the filtrate was concentrated under reducedpressure to provide title compound as yellow oil (0.4 g). ¹H NMR (300MHz, CDCl₃-d₆) δ 6.62 (m, 1H), 6.84 (d, 1H), 7.1 (t, 1H), 7.23 (m, 2H),8.3 (s, 1H).

EXAMPLE 80B N-1H-indol-4-yl-N′-[4-(trifluoromethyl)benzyl]urea

The product of Example 80A (0.16 g, 1 mmol) in THF (3 mL) was treatedwith 4-(trifluoromethyl)benzylamine (0.19 g, 1.1 mmol) at ambienttemperature. After stirring for 3 hours, hexane was added to thereaction mixture to precipitate the title compound as a solid. mp 178°C. ¹H NMR (300 MHz, DMSO-d₆) δ 4.43 (d, 2H), 6.53 (t, 1H), (6.98 m, 3H),7.26 (t, 1H), 7.57 (d, 2H), 7.62 (d, 1H), 7.71 (d, 2H), 8.37 (s, 1H),11.04 (s, 1H); MS (DCI+) m/z 334 (M+H); Anal. Calcd. For C₁₇H₁₄N₃F₃O: C,61.26; H, 4.23; N, 12.61. Found: C, 61.28, H, 3.83; N, 12.31.

EXAMPLE 81 N-1H-indol-4-yl-N′-[4-(trifluoromethoxy)benzyl]urea

4-(Trifluoromethoxy)benzylamine (0.21 g, 1.1 mmol) and the product ofExample 80A (0.16 g, 1 mmol) were treated as described in Example 80B toprovide the title compound (0.23 g). mp 177° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 4.36 (d, 2H), 6.52 (m, 1H), 6.95 (m, 3H), 7.24 (t, 1H), 7.36(d, 2H), 7.48 (d, 2H), 7.63 (dd, 1H), 8.32 (1H), 11.06 (s, 1H); MS(DCI+) m/z 349.9 (M+H)⁺; Anal. Calcd. For C₁₇H₁₄N₃F₃O₂: C, 58.63, H,4.34, N, 12.07. Found: C, 58.51, H, 3.98, N, 12.03.

EXAMPLE 82 N-[3-fluoro-4-(trifluoromethyl)benzyl]-N′-1H-indol-4-ylurea

3-Fluoro-4-(trifluoromethyl)benzylamine (0.22 g, 1.1 mmol) and theproduct of Example 80A (0.16 g, 1 mmol) were treated as described inExample 80B to provide the title compound (0.24 g). mp 198° C.; ¹H NMR(300 MHz, DMSO-d₆) δ 4.43 (d, 2H), 6.52 (m, 1H), 6.98 (m, 3H), 7.26 (m,1H), 7.39 (m, 2H), 7.57 (dd, 1H), 7.77 (t, 1H), 8.40 (s, 1H), 11.05 (s,1H); MS (DCI+) m/z 349.9 (M+H)⁺. Anal. Calcd. for C₁₇H₁₃N₃F₄O: C, 58.12;H, 3.73; N, 11.96. Found C, 58.52; H, 3.99; N, 11.55.

EXAMPLE 83 1-(4-Chloro-3-trifluoromethyl-benzyl)-3-(1H-indol-4-yl)-urea

4-Chloro-3-(trifluoromethyl)benzylamine (0.27 g, 1.1 mmol) and theproduct of Example 80A (0.16 g, 1 mmol) were treated as described inExample 80B to provide the title compound. mp 197° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 4.42 (d, 2H), 6.52 (m, 1H), 6.96 (m, 3H), 7.25 (m, 1H), 7.56(dd, 1H), 7.67 (dd, 1H), 7.70 (t, 1H), 7.81 (s, 1H), 8.37 (s, 1H), 11.06(s, 1H); MS (DCI+) m/z 368 (M+H). Anal. Calcd. for C₁₇H₁₃N₃ClF₃O: C,55.52, H, 3.56; N, 11.43. Found C, 55.46; H, 3.65; N, 11.58.

EXAMPLE 84 1-(4-Chloro-3-trifluoromethyl)-3-(1H-indol-4-yl)-urea

4-Chlorobenzylamine (0.2 g, 1.4 mmol) and the product of Example 80A(0.2 g, 1.27 mmol) were treated as described in Example 80B to providethe title compound. mp 205° C. ¹H NMR (300 MHz, DMSO-d₆) δ 4.32 (d, 2H),6.52 (m, 1H), 6.87 (m, 1H), 6.97 (m, 2H), 7.25 (m, 1H), 7.37 (m, 4H),7.6 (m, 1H), 8.30 (s, 1H), 11.06 (s, 1H). MS (DCI+) m/z 300 (M+H). Anal.Calcd. for C₁₆H₁₄N₃Cl₃O: C, 64.1 1; H, 4.71; N, 14.02. Found: C, 63.99;H, 4.70; N, 13.77.

EXAMPLE 85 N-[2-(2,4-dichlorophenyl)ethyl]-N′-1H-indol-4-ylurea

2-(2,4-Dichlorophenyl)ethylamine (0.21 g, 1.1 mmol) and the product ofExample 80A (0.16 g, 1. mmol) were treated as described in Example 80Bto provide the title compound. mp 170° C.; ¹H NMR (300 MHz, DMSO-d₆) δ2.90 (m, 2H), 3.31 (m, 2H), 6.47 (m, 2H), 6.93 (m, 2H), 7.23 (m, 1H),7.40 (m, 2H), 7.60 (m, 2H), 8.15 (s, 1H), 11.02 (s, 1H). MS (DCI+) m/z347 (M+H). Anal. Calcd. for C₁₇H₁₅N₃Cl₂O: C, 58.63; H, 4.34; N, 12.07.Found: C, 58.49; H, 4.49; N, 12.38.

EXAMPLE 86 4-(trifluoromethyl)benzyl 1H-indol-4-ylcarbamate

[4-(Trifluoromethyl)phenyl]methanol (0.09 g, 0.55 mmol) and the productof Example 80A (0.08 g, 0.5 mmol) in THF (5 mL) were heated at refluxfor 16 hours with a catalytic amount of triethylamine. The reactionmixture was concentrated under reduced pressure and the residue waspurified by chromatography on silica gel eluting with 50%hexane:ethylacetate to provide the title compound as an oil (0.09 g). ¹HNMR (300 MHz, DMSO-d₆) δ 5.32 (s, 2H), 6.73 (s, 1H), 7.0 (t, 1H), 7.11(d, 1H), 7.23 (t, 1H), 7.38 (d, 1H) 7.66 (d, 2H), 7.78 (d, 2H), 9.52 (s,1H), 11.08 (s, 1H). Anal. Calcd. for C₁₇H₁₃N₂F₃O₂: C, 61.08; H, 3.92; N,8.38. Found: C, 60.97; H, 4.21; N, 8.17.

EXAMPLE 87 4-(trifluoromethoxy)benzyl 1H-indol-4-ylcarbamate

[4-(Trifluoromethoxy)phenyl]methanol (0.13 g, 0.7 mmol) and the productof Example 80A (0.1 g, 0.63 mmol) in THF (5 mL) were heated at refluxfor 16 hours with a catalytic amount of triethylamine. The reactionmixture was concentrated under reduced pressure and the residue wastriturated with diethyl ether/hexane to provide the title compound astan crystals (0.12 g). ¹H NMR (300 MHz, DMSO-d₆) δ 5.21 (s, 2H), 6.73(s, 1H), 7.0 (t, 1H), 7.1 (d, 1H), 7.23 (t, 1H), 7.38 (dd, 1H), 7.4 (d,2H), 7.6 (d, 2H), 9.5 (s, 1H), 11.06 (s, 1H).). Anal. Calcd. forC₁₇H₁₃N₂F₃O₃.0.25 H₂O: C, 57.55; H, 3.84; N, 7.90. Found: C, 57.42; H,3.81; N, 7.32

EXAMPLE 88 N-(4-bromobenzyl)-N′-(2,3-dimethyl-1H-indol-4-yl)urea

2,3-Dimethyl-4-aminoindole (0.11 g, 0.7 mmol) in THF (3 mL) was treatedwith 1-bromo-4-(isocyanatomethyl)benzene (0.17 g, 0.8 mmol) at ambienttemperature. After stirring for 3 hours at ambient temperature, hexanewas added to the reaction mixture to precipitate the title compound as atan solid (0.12 g). mp 190° C. ¹H NMR (300 MHz, DMSO-d₆) δ 2.24 (s, 3H),2.25 (s, 3H), 4.25 (d, 2H), 6.51 (t, 1H), 6.82 (t, 1H), 6.85 (d, 2H),6.95 (m, 2H), 7.25 (d, 2H), 7.53 (d, 2H), 7.78 (s, 1H), 11.04 (s, 1H);MS (DCI+) m/z 346 (M+H)⁺; Anal. Calcd. for C₁₈H₁₈N₃BrO: C, 58.08; H,4.87; N, 11.29. Found: C, 57.97, H, 4.92; N, 11.30.

EXAMPLE 89 N-(4-bromobenzyl)-N′-1H-indazol-4-ylurea EXAMPLE 89A1H-indazol-4-amine

4-Nitro-1H-indazole (1.63 g, 10 mmol) in ethanol (100 mL) was treatedwith BiCl₃ (3.46 g, 11 mmol) followed by a portionwise addition of NaBH₄The reaction mixture was stirred at ambient temperature for 20 minutesand filtered through Celite. The filtrate was evaporated under reducedpressure and the residue was partitioned between ethyl acetate/diluteNaHCO₃ solution. The organic layer was dried over MgSO₄, filtered, andthe filtrate concentrated under reduced pressure to provide the titlecompound as a tan solid (1.0 g). ¹H NMR (300 MHz, DMSO-d₆) δ 5.64 (s,2H), 6.1 (d, 1H), 6.6 (d, 1H), 6.98 (t, 1H), 8.03 (s, 1H), 12.6 (s, 1H).

EXAMPLE 89B N-(4-bromobenzyl)-N′-1H-indazol-4-ylurea hydrochloride salt

The product of Example 89A (0.16 g, 1.2 mmol) in THF (10 mL) was treatedwith 1-bromo-4-(isocyanatomethyl)benzene (0.52 g, 2.4 mmol) at roomtemperature. After stirring for 16 hours, the reaction mixture wasconcentrated and the residue was treated with methanol (20 mL) and 3NHCl (10 mL) and heated at reflux for 3 hours. The reaction mixture wasallowed to cool to room temperature, evaporated under reduced pressure,and the residue was treated with water and the pH adjusted to 5. Theobtained compound was purified by chromatography eluting with 5% ofethanol:methylene chloride and converted to HCl salt mp 126° C. ¹H NMR(300 MHz, DMSO-d₆) δ 4.32 (d, 2H), 7.0 (t, 1H), 7.05 (d, 1H), 7.18 (t,1H), 7.3 (d, 2H), 7.55 (d, 2H), 7.61 (d, 1H), 8.16 (s, 1H), 8.92 (s,1H); Analysis Calcd for C₁₅H₁₃N₄BrO HCl: C, 47.21; H, 3.70; N, 14.68.Found C, 46.99; H, 4.08; N, 14.13.

EXAMPLE 90 N-(3,4-dichlorobenzyl)-N′-1H-indazol-4-ylurea EXAMPLE 90Amethyl 4-nitro-1H-indazole-1-carboxylate

Sodium hydride (0.3 g, 12.5 mmol ) suspended in DMF (5 mL) at 0° C. wastreated with 4-nitro-1H-indazole (1.33 g, 10 mmol). After stirring atroom temperature for 1 hour, the mixture was treated withmethylchloroformate (0.9 mL). After stirring at room temperature for 3hours, the mixture was carefully treated with water and filtered toprovide the title compound (1.2 g). ¹H NMR (300 MHz, DMSO-d₆) δ 4.1 9(s, 3H), 7.9 (t, 1H), 8.38 (d, 1H), 8.62 (d, 1H), 8.85 (s, 1H).

EXAMPLE 90B methyl 4-amino-1H-indazole-1-carboxylate

The product of Example 90A (1.66 g, 7.5 mmol) methanol (20 mL) wastreated with BiCl₃ (8.2 g, 2.6 mmol) followed by the addition of NaBH₄(1.13 g, 30.5 mmol). The reaction mixture was stirred at roomtemperature for 20 minutes, filtered through Celite, and the filtratewas evaporated under reduced pressure. The residue was partitionedbetween ethyl acetate/dilute NaHCO₃ solution. The organic phase wasseparated, dried over MgSO₄ filtered and the filtrate concentrated underreduced pressure to provide the title compound (1.2 g). ¹H NMR (300 MHz,DMSO-d₆) δ 6.1 (s, 2H), 6.41 (dd, 1H), 7.21 (m, 2H), 8.42 (s, 1H).

EXAMPLE 90C methyl4-({[(3,4-dichlorobenzyl)amino]carbonyl}amino)-1H-indazole-1-carboxylate

The product of Example 90B (0.19 g, 1 mmol) in THF (3 mL) was treatedwith 1,2-dichloro-4-(isocyanatomethyl)benzene (0.22 g, 1.1 mmol) atambient temperature. After stirring for 3 hours, hexane was added to thereaction mixture to precipitate the title compound as a tan solid (0. 25g). ¹H NMR (300 MHz, DMSO-d₆) δ 4.38 (d, 2H), 6.97 (t, 1H), 7.36 (dd,1H), 7.48 (t, 1H), 7.6 (m, 2H), 7.7 (d, 1H), 7.8 (d, 1H), 8.45 (s, 1H),9.16 (s, 1H).

EXAMPLE 90D N-(3,4-dichlorobenzyl)-N′-1H-indazol-4-ylurea

The product of Example 90C (0.25 g, 0.6 mmol) was heated at reflux inmethanol (5 mL) and 0.5N KOH (1 mL) for 0.5 hours. The reaction mixturewas allowed to cool to ambient temperature, pH was adjusted to 5, andvolume was reduced under reduced pressure. Methylene chloride and waterwas added, the phases were separated, and the organic phase concentratedunder reduced pressure to provide the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ 4.38 (d, 2H), 6.9 (t, 1H), 7.05 (d, 1H), 7.19 (t, 1H), 7.35(dd, 1H), 7.6 (m, 2H), 8.06 (s, 1H), 8.82 (s, 1H). MS (DCI+) m/z 336(M+H)⁺; Anal. Calcd. For C₁₅H₁₃N₄Cl₂O: C, 53.75; H, 3.62; N, 16.72.Found: C, 53.84, H, 3.44; N, 16.88.

EXAMPLE 97 N-(1,1′-biphenyl-4-ylmethyl)-N′-5-isoquinolinylurea

The title compound was prepared using the procedure described in Example1B using 1,1′-biphenyl-4-ylmethylamine instead of2-3-fluorophenyl)ethylamine. NMR (DMSO-d₆) δ 9.78 (s, 1H), 9.57 (s, 1H),8.69 (s, 2H), 8.53 (d, 1H), 8.11 (d, 1H), 7.87 (t, 1H), 7.64 (m, 5H),7.45 (m, 4H), 7.35 (m, 1H), 4.43 (d, 2H); MS (ESI) (M+H)⁺354.

EXAMPLE 98 N-[3-fluoro-4-(trifluoromethyl)benzyl]-N′-5-isoquinolinylurea

The title compound was prepared using the procedure described in Example1B using 3-fluoro-4-(trifluoromethyl)benzylamine instead of2-(3-fluorophenyl)ethylamine. NMR (DMSO-d₆) δ 9.78 (s, 1H), 9.74 (s,1H), 8.77 (d, 1H), 8.71 (d, 1H), 8.61 (d, 1H), 8.08 (d, 1H), 7.87 (m,2H), 7.78 (d, 1H), 7.43 (m, 2H), 4.49 (d, 2H); MS (ESI) (M+H)⁺364.

EXAMPLE 99 N-5-isoquinolin yl-N′-(3-methylbenzyl)urea

The title compound was prepared using the procedure described in Example1B using 3-methylbenzylamine instead of 2-(3-fluorophenyl)ethylamine.NMR (DMSO-d₆) δ 9.68 (s, 1H), 9.18 (s, 1H), 9.23 (s, 1H), 8.66 (d, 1H),8.37 (d, 1H), 8.48 (d, 1H), 8.04 (d, 1H), 7.85 (t, 1H), 7.35 (t, 1H),7.23 (t, 1H), 7.7.26 (m, 1H), 7.06 (m, 1H),4.28 (d, 2H), 2.31 (s, 3H);MS (ESI) (M+H)⁺291.

EXAMPLE 100N-[4-fluoro-3-(trifluoromethyl)benzyl]-N′-5-isoquinolinylurea

The title compound was prepared using the procedure described in Example61B using 4-fluoro-3-(trifluoromethyl)benzylamine instead of4-cyanobenzyl alcohol. NMR (DMSO-d₆) δ 9.31 (s, 1H), 8.84 (s, 1H), 8.65(d, 2H), 7.95 (d, 2H), 7.86 (m, 2H), 7.60 (t, 1H), 7.50 (d, 1H), 7.17(t, 1H), 4.43 (d, 2H); MS (ESI) (M+H)⁺364.

EXAMPLE 101 N-(3-chloro-4-fluorobenzyl)-N′-5-isoquinolinylurea

The title compound was prepared using the procedure described in Example61B using 3-chloro-4-fluorobenzylamine instead of 4-cyanobenzyl alcohol.NMR (DMSO-d₆) δ 9.72 (s, 1H), 9.42 (s, 1H), 8.68 (d, 1H), 8.58 (d, 2H),8.05 (d, 1H), 7.88 (t, 1H), 7.67 (m, 2H), 7.20 (m, 2H), 4.38 (d, 2H); MS(ESI) (M+H)⁺330.

EXAMPLE 102 N-5-isoquinolinyl-N′-pentylurea

The title compound was prepared using the procedure described in Example60F using 1-isocyanatopentane and 5-isoquinolinamine instead of theproduct from Example 60E and 1-bromo-4-(isocyanatomethyl)benzene. NMR(DMSO-d₆) δ 9.70 (s, 1H), 9.19 (s, 1H), 8.64 (d, 1H), 8.57 (m, 2H), 8.01(d, 1H), 7.84 (d, 1H), 7.85 (t, 1H), 6.95 (m, 1H), 3.17 (m, 2H), 2.48(m, 2H), 1.23 (m, 4H), 0.86 (M, 3H); MS (ESI) (M+H)⁺339.

EXAMPLE 103 N-5-isoquinolinyl-N′-octylurea

The title compound was prepared using the procedure described in Example60F using 1-isocyanatooctane and 5-isoquinolinamine instead of theproduct from Example 60E and 1-bromo-4-(isocyanatomethyl)benzene. NMR(DMSO-d₆) δ 9.53 (s, 1H), 9.23 (s, 1H), 8.65 (d, 1H), 8.99 (d, 1H), 8.05(d, 1H), 7.86 (t, 1H), 7.01 (m, 1H), 3.15 (m, 2H), 1.51 (m, 2H), 1.28(m, 5H), 0.83 (m, 3H); MS (ESI) (M+H)⁺300.

EXAMPLE 104 N-(1-adamantylmethyl)-N′-5-isoquinolinylurea

The title compound was prepared using the procedure described in Example61B using 1-(1-adamantyl)methanamine instead of 4-cyanobenzyl alcohol.NMR (DMSO-d₆) δ 9.68 (s, 1H), 9.20 (s, 1H), 8.64 (d, 2H), 8.60 (d, 1H),8.65 (m, 1H), 8.00 (d, 1H), 7.83 (t, 1H), 6.95 (m, 1H), 2.90 (d, 2H),1.99 (m, 2H), 1.64 (m, 5H), 1.53 (m, 5H); MS (ESI) (M+H)⁺336.

EXAMPLE 105 N-(cyclohexylmethyl)-N′-5-isoquinolinylurea

The title compound was prepared using the procedure described in Example61B using 1-cyclohexylmethanamine instead of 4-cyanobenzyl alcohol. NMR(DMSO-d₆) δ 9.70 (s, 1H), 9.18 (s, 1H), 8.67 (d, 2H), 8.57 (m, 3H), 8.00(d, 1H), 7.84 (t, 1H), 7.00 (m, 1H), 3.06 (m, 2H), 1.70 (m, 5H), 1.43(m,1H), 1.21 (m, 3H). 0.97 (m, 2H); MS (ESI) (M+H)⁺284.

619946 EXAMPLE 107N-[(6,6-dimethylbicyclo[3.1.1]hept-2-yl)methyl]-N′-5-isoquinolinylurea

The title compound was prepared using the procedure described in Example61B using [6,6-dimethylbicyclo[3.1.1]hept-2-yl]methylamine instead of4-cyanobenzyl alcohol. NMR (DMSO-d₆) δ 9.74 (s, 1H), 9.28 (s, 1H), 8.64(d, 1H), 8.60 (m, 2H), 8.03 (s, 1H), 7.85 (t, 1H), 7.08 (m, 1H), 3.17(m, 2H), 2.38 (m, 1H), 2.18 (m, 3H), 2.00 (m, 1H), 1.88 (m, 5H), 1.20(s, 3H), 1.03 (s, 3H); MS (ESI) (M+H)⁺324.

EXAMPLE 108 N-5-isoquinolinyl-N′-[4-(1-pyrrolidinyl)benzyl]urea

The title compound was prepared using the procedure described in Example61B using 4-(1-pyrrolidinyl)benzylamine instead of 4-cyanobenzylalcohol. NMR (DMSO-d₆) δ 9.81 (s, 1H), 9.58 (s, 1H), 8.80 (d, 1H), 8.71(m, 2H), 8.11 (d, 1H), 7.93 (t, 1H), 7.48 (bs, 1H), 7.20 (m, 2H), 6.65(m, 2H), 4.43 (d, 2H), 3.13 (m, 4H), 1.97 (m, 4H); MS (ESI) (M+H)⁺347.

EXAMPLE 109 N-[4-(1-azepanyl)benzyl]-N′-5-isoquinolinylurea

The title compound was prepared using the procedure described in Example61B using 4-(1-azepanyl)benzylamine instead of 4-cyanobenzyl alcohol.NMR (DMSO-d₆) δ 9.80 (s, 1H), 9.58 (s, 1H), 8.79 (m, 1H), 8.71 (m, 2H),8.11 (d, 1H), 7.95 (t, 1H), 7.48 (bs, 1H), 7.20 (m, 2H), 6.85 (bs, 2H),4.23 (d, 2H), 3.45 (m, 4H), 1.69 (bs, 4H), 1.50 (bs, 4H); MS (ESI)(M+H)⁺375.

EXAMPLE 110 N-[3-fluoro-4-(1-pyrrolidinyl)benzyl]-N′-5-isoquinolinylurea

The title compound was prepared using the procedure described in Example61B using 3-fluoro-4-(1-pyrrolidinyl)benzylamine instead of4-cyanobenzyl alcohol. NMR (DMSO-d₆) δ 9.82 (s, 1H), 9.72 (s, 1H), 8.85(d, 1H), 8.70 (m, 2H), 8.14 (d, 1H), 7.95 (t, 1H), 7.64 (bs, 1H), 7.03(m, 2H), 6.75 (t, 1H), 4.25 (d, 2H), 3.30 (m, 4H), 1.74 (m, 4H); MS(ESI) (M+H)⁺365.

EXAMPLE 111 N-[4-(1-azepanyl)-3-fluorobenzyl]-N′-5-isoquinolinylurea

The title compound was prepared using the procedure described in Example61B using 4-(1-azepanyl)-3-fluorobenzylamine instead of 4-cyanobenzylalcohol. NMR (DMSO-d₆) δ 9.85 (s, 1H), 9.77 (s, 1H), 8.71 (m, 2H), 8.13(d, 1H), 7.94 (t, 1H), 7.77 (bs, 1H), 7.64 (bs, 1H), 7.10-6.90 (m, 2H),4.28 (d, 2H), 3.35 (m, 4H), 1.77 (m, 4H), 1.58 (m, 4H); MS (ESI)(M+H)⁺393.

EXAMPLE 112 N-[4-(1-azocanyl)benzyl]-N′-5-isoquinolinylurea

The title compound was prepared using the procedure described in Example61B using 4-(1-azocanyl)benzylamine instead of 4-cyanobenzyl alcohol.NMR (DMSO-d₆) δ 9.85 (s, 1H), 9.67 (s, 1H), 8.70 (s, 1H), 8.77 (m, 2H),8.13 (s, 1H), 7.95 (t, 1H), 7.45 (bs, 1H), 7.17 (d, 2H), 6.63 (d, 2H),4.23 (d, 2H), 3.43 (m, 6H), 1.68 (m, 3H), 1.44 (m, 5H); MS (ESI)(M+H)⁺389.

EXAMPLE 114 N-1H-indazol-4-yl-N′-[4-(1-piperidinyl)benzyl]urea

The title compound was prepared using the procedure described in Example89B using 1-[4-(isocyanatomethyl)phenyl]piperidine instead of1-bromo-4-(isocyanatomethyl)benzene. NMR (DMSO-d₆) δ 9.23 (s, 1H), 9.30(s, 1H), 7.78 (d, 2H), 7.64 (d, 1H), 7.63 (d, 2H), 7.53 (s, 1H), 7.38(bs, 1H), 7.19 (t, 1H), 7.06 (d, 1H), 4.39 (d, 2H), 3.53 (m, 4H), 1.97(bs, 4H), 1.64 (bs, 2H); MS (ESI) (M+H)⁺350.

EXAMPLE 115 N-[3-fluoro-4-(1-piperidinyl)benzyl]-N′-1H-indazol-4-ylurea

The title compound was prepared using the procedure described in Example89B using 1-[2-fluoro-4-(isocyanatomethyl)phenyl]piperidine instead of1-bromo-4-(isocyanatomethyl)benzene. NMR (DMSO-d₆) δ 9.17 (s, 1H), 8.28(s, 1H), 7.63 (d, 1H), 7.40-7.15 (m, 6H), 7.05 (d, 1H), 4.37 (s, 2H),3.17 (m, 4H), 1.77 (m, 4H), 1.58 (m, 2H).4H), 1.64 (bs, 2H); MS (ESI)(M+H)⁺368.

EXAMPLE 116 N-1H-indazol-4-yl-N′-[4-(1-pyrrolidinyl)benzyl]urea

The title compound was prepared using the procedure described in Example89B using 1-[4-(isocyanatomethyl)phenyl]pyrrolidine instead of1-bromo-4-(isocyanatomethyl)benzene. NMR (DMSO-d₆) δ 8.83 (s, 1H), 8.15(s, 1H), 8.01 (bs, 1H), 7.63 (d, 1H), 7.21 (m, 3H), 7.04 (d, 1H), 6.70(bs, 1H), 6.63 (m, 1H), 6.56 (d, 1H), 4.12 (d, 2H), 3.13 (m, 4H), 1.97(m, 4H); MS (ESI) (M+H)⁺336.

EXAMPLE 117 N-[3-fluoro-4-(1-pyrrolidinyl)benzyl]-N′-1H-indazol-4-ylurea

The title compound was prepared using the procedure described in Example89B using 1-[2-fluoro-4-(isocyanatomethyl)phenyl]pyrrolidine instead of1-bromo-4-(isocyanatomethyl)benzene. NMR (DMSO-d₆) δ 9.89 (s, 1H), 8.17(s, 1H), 7.63 (d, 1H), 7.19 (t, 1H), 7.07 (m, 1H), 7.02 (d, 1H), 6.99(s, 1H), 6.93 (bs, 2H), 6.74 (t, 1H), 4.23 (s, 2H), 3.29 (m, 4H), 1.87(m, 4H); MS (ESI) (M+H)⁺354.

EXAMPLE 118 N-[4-(1-azepanyl)benzyl]-N′-1H-indazol-4-ylurea

The title compound was prepared using the procedure described in Example89B using 1-[4-(isocyanatomethyl)phenyl]azepane instead of1-bromo-4-(isocyanatomethyl)benzene. NMR (DMSO-d₆) δ 8.86 (s, 1H), 8.17(s, 1H), 8.00 (bs, 1H), 7.64 (d, 1H), 7.20 (m, 3H), 7.02 (d, 1H), 6.25(bs, 2H), 6.70 (d, 1H), 4.21 (s, 2H), 1.88 (m, 6H), 1.47 (m, 6H); MS(ESI) (M+H)⁺364.

764293 EXAMPLE 119N-[4-(1-azepanyl)-3-fluorobenzyl]-1-N′-1H-indazol-4-ylurea

The title compound was prepared using the procedure described in Example89B using 1-[2-fluoro-4-(isocyanatomethyl)phenyl]azepane instead of1-bromo-4-(isocyanatomethyl)benzene. NMR (DMSO-d₆) δ 9.04 (s, 1H), 8.13(s, 1H), 7.63 (d, 1H), 7.19 (t, 1H), 7.10 (s, 1H), 7.02 (d, 4H), 4.23(s, 2H), 3.37 (m, 4H), 1.79 (m, 4H), 1.57 (m, 4H); MS (ESI) (M+H)⁺382.

EXAMPLE 120N-(1-methyl-1H-indazol-4-yl)-N′-[4-(1-piperidinyl)benzyl]urea

The title compound was prepared using the procedure described in Example89B using 1-[4-(isocyanatomethyl)phenyl]piperidine and1-methyl-1H-indazol-4-amine instead of1-bromo-4-(isocyanatomethyl)benzene and the product from Example 89A.NMR (DMSO-d₆) δ 9.43 (s, 1H), 8.37 (s, 1H), 7.82 (d, 2H), 7.69 (d, 1H),7.63 (m, 3H), 7.22 (t, 1H), 7.11 (t, 1H), 4.40 (d, 2H), 3.99 (s, 3H),3.50 (m, 4H), 1.98 (m, 4H), 1.67 (m, 2H); MS (ESI) (M+H)⁺364.

EXAMPLE 121N-[3-fluoro-4-(1-piperidinyl)benzyl]-N′-(1-methyl-1H-indazol-4-yl)urea

The title compound was prepared using the procedure described in Example89B using 1-[2-fluoro-4-(isocyanatomethyl)phenyl]piperidine and1-methyl-1H-indazol-4-amine instead of1-bromo-4-(isocyanatomethyl)benzene and the product from Example 89A.NMR (DMSO-d₆) δ 9.19 (s, 1H), 8.22 (s, 1H), 7.25 (m, 4H), 7.18 (d, 2H),4.31 (s, 2H), 4.00 (s, 3H), 3.15 (m, 4H), 1.77 (m, 4H), 1.66 (m, 2H); MS(ESI) (M+H)⁺382.

EXAMPLE 122N-(1-methyl-1H-indazol-4-yl)-N′-[4-(1-pyrrolidinyl)benzyl]urea

The title compound was prepared using the procedure described in Example89B using 1-[4-(isocyanatomethyl)phenyl]pyrrolidine and1-methyl-1H-indazol-4-amine instead of1-bromo-4-(isocyanatomethyl)benzene and the product from Example 89A.NMR (DMSO-d₆) δ 8.98 (s, 1H), 8.16 (s, 1H), 7.63 (d, 1H), 7.13 (m, 3H),7.12 (d, 1H), 6.94 (m, 1H), 6.73 (bs, 2H), 4.23 (s, 2H), 3.99 (s, 3H),3.24 (m, 4H), 1.98 (m, 4H); MS (ESI) (M+H)⁺350.

764300 EXAMPLE 123N-[3-fluoro-4-(1-pyrrolidinyl)benzyl]-N′-(1-methyl-1H-indazol-4-yl)urea

The title compound was prepared using the procedure described in Example89B using 1-[2-fluoro-4-(isocyanatomethyl)phenyl]pyrrolidine and1-methyl-1H-indazol-4-amine instead of1-bromo-4-(isocyanatomethyl)benzene and the product from Example 89A.NMR (DMSO-d₆) δ 8.98 (s, 1H), 8.18 (s, 1H), 7.63 (d, 1H), 7.12 (t, 1H),7.10 (m, 2H), 7.01 (m, 2H), 6.75 (t, 1H), 4.22 (s, 2H), 3.99 (s, 3H),3.30 (m, 4H), 1.89 (m, 4H); MS (ESI) (M+H)⁺368.

EXAMPLE 124 N-[4-(1-azepanyl)benzyl]-N′-(1-methyl-1H-indazol-4-yl)urea

The title compound was prepared using the procedure described in Example89B using 1-[4-(isocyanatomethyl)phenyl]azepane and1-methyl-1H-indazol-4-amine instead of1-bromo-4-(isocyanatomethyl)benzene and the product from Example 89A.NMR (DMSO-d₆) δ 8.97 (s, 1H), 8.18 (s, 1H), 7.65 (d, 1H), 7.14 (m, 4H),7.11 (d, 1H), 6.95 (bs, 2H), 4.23 (s, 2H), 3.99 (s, 3H), 3.27 (m, 4H),1.90 (m, 4H), 1.53 (m, 4H); MS (ESI) (M+H)⁺378.

EXAMPLE 125N-[4-(1-azepanyl)-3-fluorobenzyl]-N′-(1-methyl-1H-indazol-4-yl)urea

The title compound was prepared using the procedure described in Example89B using 1-[2-fluoro-4-(isocyanatomethyl)phenyl]azepane and1-methyl-1H-indazol-4-amine instead of1-bromo-4-(isocyanatomethyl)benzene and the product from Example 89A.NMR (DMSO-d₆) δ 9.03 (s, 1H), 8.19 (s, 1H), 7.67 (d, 1H), 7.24 (t, 1H),7.12-6.95 (m, 5H), 4.22 (s, 2H), 3.99 (s, 3H), 3.35 (m, 4H), 1.78 (m,4H), 1.55 (m, 4H); MS (ESI) (M+H)⁺396.

EXAMPLE 126 4-methylbenzyl 5-isoquinolinylcarbamate

The title compound was prepared using the procedure described in Example1B using 4-methylbenzyl alcohol instead of 2-(3-fluorophenyl)ethylamine.¹H NMR (300 MHz, d₆-DMSO) 9.82 (s, 1H), 9.31 (s, 1H), 8.50 (d, 1H), 7.93(m, 3H), 7.68 (t, 1H), 7.37 (d, 2H), 7.25 (d, 2H), 5.19 (s, 2H), 2.32(s, 3H); MS (DCI/NH₃) m/e 293 (M+H)⁺.

EXAMPLE 127 N-5-isoquinolinyl-2-[4-(trifluoromethyl)phenyl]hydrazinecarboxamide

The title compound was prepared using the procedure described in Example61B using 4-trifluoromethylphenyl hydrazine instead of 4-cyanobenzylalcohol. ¹H NMR (300 MHz, d₆-DMSO) 9.80 (m, 2H), 9.10 (broad s, 1H),8.90-8.43 (m, 3H), 8.40 (broad s, 1H), 8.20 (d, 1H), 7.93 (t, 1H), 7.58(d, 2H), 6.96 (d, 2H); MS (DCI/NH₃) m/e 347 (M+H)⁺; Anal. Calcd. ForC₁₇H₁₃N₄OF₃.1.0 HCl 0.1 H₂O: C 53.09; H 3.72; N 14.57. Found: C 52.80; H3.81; N, 14.51.

EXAMPLE 128 4-bromobenzyl 5-isoquinolinylcarbamate

The title compound was prepared using the procedure described in Example1B using 4-bromobenzyl alcohol instead of 2-(3-fluorophenyl)ethylamine.¹H NMR (300 MHz, d₆-DMSO) 10.23 (s, 1H), 9.86 (s, 1H), 8.69 (d, 1H),8.50 (d, 1H), 8.30 (d, 2H), 7.98 (t, 1H), 7.60 (m, 2H), 7.44 (d, 2H),5.20 (s, 2H); MS (DCI/NH₃) m/e 357 (M+H)⁺; Anal. Calcd. ForC₁₇H₁₃N₂O₂Br. 1.0 HCl: C, 51.87; H 3.58; N 7.12. Found: C 51.95; H 3.45;N 7.03.

EXAMPLE 129 N-benzhydryl-N′-5-isoquinolinylurea

The title compound was prepared using the procedure described in Example61B using benzhydrylamine instead of 4-cyanobenzyl alcohol. ¹H NMR (300MHz, d₆-DMSO) 9.26 (s, 1H), 8.78 (s, 1H), 8.57 (d, 1H), 8.31 (m, 1H),7.94 (d, 1H), 7.70 (d, 1H), 7.60 (m, 2H), 7.38 (m, 8H), 7.27 (m, 2H),6.02 (d, 1H); MS (DCI/NH₃) m/e 354 (M+H)⁺; Anal. Calcd. For C₂₃H₁₉N₃O.0.1 H₂O: C 77.77; H 5.45; N 11.83. Found: C 77.52; H 5.30; N 11.98.

EXAMPLE 130 N-[(1S)-1-(4-bromophenyl)ethyl]-N′-5-isoquinolinylurea

The title compound was prepared using the procedure described in Example61B using (1S)-1-(4-bromophenyl)ethanamine instead of 4-cyanobenzylalcohol. ¹H NMR (300 MHz, d₆-DMSO) 9.78 (s, 1H), 9.46 (s, 1H), 8.70 (s,2H), 8.59 (d, 1H), 8.04 (d, 1H) 7.84 (t, 1H), 7.75 (d, 1H), 7.58 (d,2H), 7.40 (d, 2H), 4.85 (m, 1H), 1.40 (d, 3H); MS (DCI/NH₃) m/e 370(M+H)⁺. Anal. Calcd. For C₁₈H₁₆N₃OBr. 1.2 HCl: C 52.22; H 4.19; N 10.15.Found: C 51.86; H 4.28; N, 9.78.

EXAMPLE 131 N-[(1R)-1-(4-bromophenyl)ethyl]-N′-5-isoquinolinylurea

The title compound was prepared using the procedure described in Example61B using (1R)-1-(4-bromophenyl)ethanamine instead of 4-cyanobenzylalcohol. ¹H NMR (300 MHz, d₆-DMSO) 9.65 (s, 1H), 9.46 (s, 1H), 8.71 (s,2H), 8.60 (d, 1H), 8.04 (d, 1H), 7.84 (t, 1H), 7.78 (d, 1H), 7.58 (d,2H), 7.38 (d, 2H), 4.87 (m, 1H), 1.40 (d, 3H); MS (DCI/NH₃) m/e 370(M+H)⁺; Anal. Calcd. For C₁₈H₁₆N₃OBr. 1.1 HCl: C 52.69; H 4.20; N 10.24.Found: C 52.52; H 4.28; N 10.00.

EXAMPLE 132 N-(4-bromobenzyl)-2-(3-methyl-5-isoquinolinyl)acetamideEXAMPLE 132A 5-allyl-3-methylisoquinoline

3-Methyl-5-bromoisoquinoline (1.0 g, 4.5 mmol), tributylallyltin (1.6mL, 5.0 mmol), and dichirobis(tri-o-tolylphosphine)palladium (II) werecombined in toluene (100 mL) and refluxed for 14 hours. The mixture wascooled, diluted with ethyl acetate, and washed twice with aqueous NH₄Cl.The organic phase was separated, concentrated, and the residue waspurified by chromatography (ethyl acetate:hexanes, 30:70) to provide thetitle compound. ¹H NMR (300 MHz, d₆-DMSO) 9.21 (s, 1H), 8.00 (d, 1H),7.63 (m, 2H), 7.58 (m, 1H), 4.18 (s, 2H), 3.62 (s, 3H), 2.62 (s 3H). MS(DCI/NH₃) m/e 216 (M+H)⁺.

EXAMPLE 132B methyl (3-methyl-5-isoquinolinyl)acetate

The product from Example 132A (0.8 g, 4.37 mmol) in CH₂CL₂(40 mL) and2.5 MNaOH in MeOH (9 mL, 22 mmol, 5 eq.) was ozonized at −78° C. for 3hours. The mixture was diluted with diethyl ether and washed withaqueous NH₄Cl. The organic phase was separated, concentrated, and theresidue was purified by chromatography (ethyl acetate:hexanes, 40:60) toprovide the title compound. ¹H NMR (300 MHz, d₆-DMSO) 9.20 (s, 1H), 7.92(d, 1H), 7.73 (s, 1H), 7.55 (m, 2H), 6.08 (m, 1H), 5.15-5.04 (m, 2H),3.80 (d, 2H), 2.63 (s, 3H); MS (DCI/NH₃) m/e 184 (M+H)⁺.

EXAMPLE 132C N-(4-bromobenzyl)-2-(3-methyl-5-isoquinolinyl)acetamide

4-Bromobenzylamine (3.06 mmol) in CH₂Cl₂ (30 mL) was treated with 2MMe₃Al (1.53 mL, 3.06 mmol) in toluene. After 30 minutes, the mixture wastreated with the product from Example 132B (0.33 g, 1.53 mmol) andrefluxed for 16 hours. The mixture was cooled, quenched with 1N HCl,diluted with ethyl acetate, and washed with water, aqueous NaHCO₃ andaqueous NH₄Cl. The organic phase was evaporated and the residuedissolved in CH₂Cl₂:MeOH and 1M HCl (3 mL) in diethyl ether. Afterstirring for 2 hours, the mixture was concentrated under reducedpressure to provide the title compound. ¹H NMR (300 MHz, d₆-DMSO) 9.75(s, 1H), 8.92 (m, 1H), 8.30 (m, 2H), 8.00 (d, 1H), 7.82 (m, 1H), 7.60(d, 2H), 7.20 (d, 2H), 4.22 (d, 2H), 4.08 (s, 2H), 2.78 (s, 3H); MS(DCI/NH₃) m/e 369 (M+H)⁺; Anal. Calcd. For C₁₉H₁₇N₂OBr. 2.0 HCl. 1.7H₂O: C 48.27; H 4.78; N 5.92. Found: C 47.89; H 4.21; N 6.32.

EXAMPLE 133 N-(4-bromobenzyl)-2-(5-isoquinolinyl)acetamide EXAMPLE 133A5-allylisoquinoline

The title compound was prepared using the procedure described in Example132A using 5-bromoisoquinoline instead of 3-methyl-5-bromoisoquinoline.

EXAMPLE 133B methyl 5-isoquinolinylacetate

The title compound was prepared using the procedure described in Example132B using the product from Example 133A instead of the product fromExample 132A.

EXAMPLE 133C N-(4-bromobenzyl)-2-(5-isoquinolinyl)acetamide

The title compound was prepared using the procedure described in Example132C using the product from Example 133B instead of the product fromExample 132B. ¹H NMR (300 MHz, d₆-DMSO) 9.78 (s, 1H), 8.85 (m, 1H), 8.68(d, 1H), 8.42 (d, 1H), 7.90 (d, 1H), 8.01 (d, 1H), 7.94 (m, 1H), 7.52(d, 2H), 7.20 (d, 2H), 4.22 (d, 2H), 4.10 (s, 2H); MS (DCI/NH₃) m/e 355(M+H)⁺; Anal. Calcd. For C₁₈H₁₅N₂OBr. 1.0 HCl. 0.3 H₂O: C 54.44; H 4.21;N 7.05. Found: C 54.11; H 4.18; N 6.86.

EXAMPLE 134 N-[1-(4-bromophenyl)ethyl]-2-(5-isoquinolin yl)acetamide

The title compound was prepared using the procedure described in Example132C using the product from Example 133B and 1-(4-bromophenyl)ethanamineinstead of the product from Example 132B and 4-bromobenzylamine. ¹H NMR(300 MHz, d₆-DMSO) 9.81 (s, 1H), 9.00 (d, 1H), 8.70 (d, 1H), 8.48 (d,1H), 840 (d, 1H), 8.04 (d, 1H), 7.92 (m, 1H), 7.51 (d, 2H), 7.23 (d,2H), 4.84 (m, 1H), 4.10 (s, 2H), 1.35 (d, 3H). MS (DCI/NH₃) m/e 369(M+H)+; Anal. Calcd. For C₁₉H₁₇N₂OBr. 1.0 HCl. 1.0 H₂O: C 53.86; H 4.76;N 6.61. Found: C 53.47; H 4.53; N 6.76.

EXAMPLE 135N-[1-(4-bromophenyl)ethyl]-2-(3-methyl-5-isoquinolinyl)acetamide

The title compound was prepared using the procedure described in Example132C using 1-(4-bromophenyl)ethanamine instead of 4-bromobenzylamine. ¹HNMR (300 MHz, d₆-DMSO) 9.68 (s, 1H), 8.84 (d, 1H), 8.24 (m, 2H), 7.92(d, 1H), 7.80 (m, 1H), 7.50 (d, 2H), 7.28 (d, 2H), 4.02 (s, 2H), 2.75(s, 3H), 1.38 (s, 3H); MS (DCI/NH₃) m/e 383 (M+H)⁺; Anal. Calcd. ForC₂₀H₁₉N₂OBr. 0.9 HCl: C 57.73; H 4.82; N 6.73. Found: C 57.69; H 4.80; N4.80; N 6.07

EXAMPLE 136N-5-isoquinolinyl-N′-{1-[4-(trifluoromethyl)phenyl]ethyl}urea EXAMPLE136A 1-[4-(trifluoromethyl)phenyl]ethanone oxime

4-Trifluoromethylacetophenone (13.6 g, 72.3 mmol) andO-methylhydroxylamine hydrochloride were combined in pyridine (100 mL)and stirred at ambient temperature for 16 hours. The mixture wasconcentrated under reduced pressure and the residue was suspended indiethyl ether. The suspension was filtered and the filter cake waswashed with diethyl ether. The filtrate was washed with water, 1N HCl,and water. The organic phase was concentrated to provide the titlecompound. ¹H NMR (300 MHz, d₆-DMSO) 7.90-7.68 (m, 4H), 3.97 and 3.78(2S, 1H), 2.20 and 2.17 (2s, 3H); MS (DCI/NH₃) m/e 218 (M+H)⁺.

EXAMPLE 136B 1-[4-(trifluoromethyl)phenyl]ethanamine

The product from Example 136A (21.0 g, 100 mmol) in MeOH (220 mL) andammonia (30 mL) was treated with 10% Pd/C under 60 psi of hydrogen gasfor 2 hours. The mixture was filtered and the filtrate was concentratedto provide the title compound. ¹H NMR (300 MHz, d₆-DMSO) 7.60 (q, 4H),4.07 (q, 1H), 3.28 (broad s, 2H), 1.24 (d, 3H); MS (DCI/NH₃) m/e 190(M+H)⁺.

EXAMPLE 136CN-5-isoquinolinyl-N′-{1-[4-(trifluoromethyl)phenyl]ethyl}urea

The title compound was prepared using the procedure described in Example61B using the product from Example 136B instead of 4-cyanobenzylalcohol. ¹H NMR (300 MHz, d₆-DMSO) 9.80 (s, 1H), 9.75 (s, 1H), 8.90 (d,1H), 8.73 (d, 1H), 8.63 (d, 1H), 8.08 (m, 2H), 7.90 (t, 1H), 7.77 (d,2H), 7.64 (d, 2H), 4.95 (m, 1H), 1.41 (d, 3H); MS (DCI/NH₃) m/e 360(M+H)⁺; Anal. Calcd. For C₁₉H₁₆N₃OF₃. 1.0 HCl. 0.3 H₂O: C 56.88; H 4.42;N 10.47. Found: C 56.61; H 4.49; N 10.28.

EXAMPLE 138(−)N-5-isoquinolinyl-N′-{(1S)-1-[4-(trifluoromethyl)phenyl]ethyl}ureaEXAMPLE 138A(1R)-2-oxo-1-phenyl-2-({1-[4-(trifluoromethyl)phenyl]ethyl}amino)ethylacetate

1-[4-(Trifluoromethyl)phenyl]ethanamine (37.5 g, 198.4 mmol) and(R)-acetylmandelic acid (40.4 g, 208.3 mmol, 1.05 eq.) were combined inDMAP (0.7 g, 5.7 mmol) and treated with DCC (45.0 g, 218 mmol). Afterstirring overnight at ambient temperature, the mixture was filteredthrough a plug of silica. The filtrate was concentrated and the residuewas purified by chromatography on Biotage Flash 75 column (ethylacetate:hexanes, 25:75) to provide a faster running diastereomer and aslower running diastereomer. (fast diastereomer) ¹H NMR (300 MHz, CDCl₃)7.58 (d, 2H), 7.39 (m, 7H), 6.30 broad (d, 1H), 6.08 (s, 1H), 5.18 (m,1H), 2.20 (s, 3H), 1.29 (d, 3H); MS (DCI/NH₃) m/e 366 (M+H)⁺. (slowdiastereomer) ¹H NMR (300 MHz, CDCl₃) 7.58 (d, 2H), 7.40 (m, 5H), 7.31(d, 2H), 6.21 (broad d, 1H), 6.06 (s, 1H), 5.18 (m, 1H), 2.20 (s, 3H),1.50 (d, 3H); MS (DCI/NH₃) m/e 366 (M+H)⁺.

EXAMPLE 138B (−)1-[4-(trifluoromethyl)phenyl]ethanamine

The faster running diastereomer from Example 138A (29.2 g, 80 mmol) wastreated with 48% aqueous HBr (350 mL) and water (50 mL) and was refluxeifor 16 hours. The mixture was cooled and extracted with diethyl ether.The aqueous phase was basified with 2N NaOH (pH 12-13) and extractedwith diethyl ether. The organic phase was concentrated to provide thetitle compound. 94% ee (by Mosher amide NMR). [α]_(D)−19.1° (c 1.15;MeOH); ¹H NMR (300 MHz, CDCl₃) 7.60 (d, 2H), 7.47 (d, 2H), 4.20 (m, 1H),1.65 (br s, 2H), 1.40 (s, 3H); MS (DCI/NH₃) m/e 190 (M+H)⁺.

EXAMPLE 138C (+) 1-[4-(trifluoromethyl)phenyl]ethanamine

The slower running diastereomer from Example 138A (29.2 g, 80 mmol) wastreated with 48% aqueous HBr (350 mL) and water (50 mL) and was refluxedfor 16 hours. The mixture was cooled and extracted with diethyl ether.The aqueous phase was basified with 2N NaOH (pH 12-13) and extractedwith diethyl ether. The organic phase was concentrated to provide thetitle compound. [α]_(D)+20.5° (c 1.47; MeOH). 94% ee (Mosher amide NMR);¹H NMR (300 MHz, CDCl₃) 7.60 (d, 2H), 7.47 (d, 2H), 4.20 (m, 1H), 1.60(br s, 2H), 1.40 (s, 3H); MS (DCI/NH₃) m/e 190 (M+H)⁺.

EXAMPLE 138D (−)N-5-isoquinolinyl-N′-{(1S)-1-[4-(trifluoromethyl)phenyl]ethyl}urea

The title compound was prepared using the procedure described in Example61B using the product from Example 138B instead of 4-cyanobenzylalcohol. ¹H NMR (300 MHz, d₆-DMSO) 9.90 (s, 1H), 9.83 (s, 1H), 9.00 (d,1H), 8.72 (d, 1H), 8.66 (d, 1H), 8.23 (d, 1H), 8.10 (d, 1H), 7.90 (t,1H), 7.72 (d, 2H), 7.64 (d, 2H), 4.98 (m, 1H), 1.43 (d, 3H); MS(DCI/NH₃) m/e 360 (M+H)⁺; [α]_(D)−18.4° (c 1.24; MeOH); Anal. Calcd. ForC₁₉H₁₆N₃OF₃. 1.0 HCl. 0.7 H₂O: C 55.88; H 4.54; N 10.29. Found: C 55.70;H 4.40; N 10.12.

EXAMPLE 139 (+)N-5-isoquinolinyl-N′-{(1S)-1-[4-(trifluoromethyl)phenyl]ethyl}urea

The title compound was prepared using the procedure described in Example61B using the product from Example 138C instead of 4-cyanobenzylalcohol. ¹H NMR (300 MHz, d₆-DMSO) 9.90 (s, 2H), 8.98 (d, 1H), 8.72 (d,1H), 8.66 (d, 1H), 8.19 (d, 1H), 8.10 (d, 1H), 7.90 (t, 1H), 7.72 (d,2H), 7.64 (d, 2H), 4.98 (m, 1H), 1.43 (d, 3H); MS (DCI/NH₃) m/e 360(M+H)⁺. [α]_(D)+17.0° (c 1.55; MeOH); Anal. Calcd. For C₁₉H₁₆N₃OF₃. 1.0HCl. 0.4 H₂O: C 56.63; H 4.45; N 10.43. Found: C 56.43; H 4.52; N 10.24.

EXAMPLE 140 N-[1-(4-tert-butylphenyl)ethyl]-N′-5-isoquinolinylureaEXAMPLE 140A 1-(4-tert-butylphenyl)ethanamine

The title compound was prepared using 1-(4-tertbutylphenyl)ethanone andthe procedures described in Examples 136A and 136B

EXAMPLE 140B N-[1-(4-tert-butylphenyl)ethyl]-N′-5-isoquinolinylurea

The title compound was prepared using the procedure described in Example61B using the product from Example 140A instead of 4-cyanobenzylalcohol. ¹H NMR (300 MHz, d₆-DMSO) 9.88 (s, 1H), 9.72 (broad s, 1H),8.90 (d, 1H), 8.70 (d, 1H), 8.64 (d, 1H), 8.07 (d, 1H), 7.87 (t, 1H),7.78 (d, 1H), 7.38 (m, 4H), 4.94 (m, 1H), 1.42 (d, 3H), 1.27 (s, 9H); MS(DCI/NH₃) m/e 348 (M+H)⁺; Anal. Calcd. For C₂₂H₂₅N₃O. 1.0 HCl. 0.6 H₂O:C 66.94; H 6.96; N 10.65. Found: C 66.69; H 6.92; N 10.52.

EXAMPLE 141N-{cyclopropyl[4-(trifluoromethyl)phenyl]methyl}-N′-5-isoquinolinylureaEXAMPLE 141A N-methoxy-N-methyl-4-(trifluoromethyl)benzamide

4-(Trifluoromethyl)benzoyl chloride (5.0 g, 23.9 mmol) andN,O-dimethylhydroxylamine hydrochloride (2.55 g, 26.3 mmol, 1.1 eq.)were combined in CH₂Cl₂ (200 mL) at 0° C. and treated with pyridine (4.3mL, 52.6 mmol). After stirring for 2 hours, the mixture was allowed toattain ambient temperature, diluted with diethyl ether and washed withwater, aqueous HCl, and water the organic phase was separated andconcentrated to provide the title compound which was used directly inthe next step. ¹H NMR (300 MHz, d₆-DMSO) 7.90 (m, 4H), 3.52 (s, 3H),3.28 (s, 3H); MS (DCI/NH₃) m/e 234 (M+H)⁺.

EXAMPLE 141B cyclopropyl[4-(trifluoromethyl)phenyl]methanone

The product from Example 141A (1.02 g, 4.38 mmol) in THF (50 mL) at 0°C. was treated with 0.8M solution of cyclopropylmagnesium bromide (7.1mL, 5.7 mmol, 1.3 q.) in THF. After stirring for 1 hour, the mixture wastreated with water (5 mL), 3N HCl (0.5 mL), diluted with diethyl ether,and washed with water. The organic phase was separated, evaporated, andand the residue was purified by chromatography (ethyl acetate:hexanes,5:95) to provide the title compound. ¹H NMR (300 MHz, d₆-DMSO) 8.24 (d,2H), 7.92 (d, 2H), 2.92 (m, 1H), 1.10 (m, 4H).

EXAMPLE 141C 1-cyclopropyl-1-[4-(trifluoromethyl)phenyl]methanamine

The title compound was prepared using the product from Example 141B andthe procedures described in Examples 136A and 136B. ¹H NMR (300 MHz,d₆-DMSO) 7.92 (m, 4H), 3.24 (d, 1H), 1.92 (broad s, 2H), 0.93 (m, 1H),0.50-0.27 (m, 4H); MS (DCI/NH₃) m/e. 216 (M+H)⁺.

EXAMPLE 141DN-{cyclopropyl[4-(trifluoromethyl)phenyl]methyl}-N′-5-isoquinolinylurea

The title compound was prepared using the procedure described in Example61B using the product from Example 141C instead of 4-cyanobenzylalcohol. ¹H NMR (300 MHz, d₆-DMSO) 9.78 (s, 1H), 9.63 (s, 1H), 8.80 (d,1H), 8.70 (d, 1H), 8.60 (d, 1H), 8.07 (m, 2H), 7.86 (t, 1H), 7.73 (d,2H), 7.63 (d, 2H), 4.37 (t, 1H), 1.10 (m, 1H), 0.60-0.40 (m, 4H); MS(DCI/NH₃) m/e 386 (M+H)⁺; Anal. Calcd. For C₂₁H₁₈N₃OF₃. 1.0 HCl. 0.25H₂O: C 59.16; H, 4.81; N 9.86. Found: C 58.81; H, 4.76; N 9.62.

EXAMPLE 142(2E)-N-5-isoquinolinyl-3-[4-(trifluoromethyl)phenyl]-2-butenamideEXAMPLE 142A ethyl (2E)-3-[4-(trifluoromethyl)phenyl]-2-butenoate

A suspension of 98% NaH (0.81 g, 33.7 mmol) in THF (100 mL) at ambienttemperature was treated with triethyl phosphonate (6.9 g, 31 mmol)dropwise and the resulting mixture was stirred for 15 minutes. Themixture was treated with 1-[4-(trifluoromethyl)phenyl]ethanone (5.0 g,26.6 mmol) portion wise and refluxed for 6 hours. After cooling toambient temperature, the mixture was quenched with aqueous NH₄Cl,diluted with diethyl ether, and washed with water and aqueous NH₄Cl. Theorganic phase was separated, concentrated, and the residue purified bychromatography (ethyl acetate:hexanes, 2:98) to provide the (E) isomer(3.4 g, 50%) and the (Z) isomer (1.3 g, 19%). Geometry of the doublebond was established by NOE studies. (E) isomer: ¹HNMR for (300 MHz,d₆-DMSO) 7.78 (m, 4H), 6.25 (m, 1H), 4.19, (q, 2H), 2.51, s, 3H), 1.22(t, 3H); MS (DCI/NH₃) m/e 259 (M+H)⁺.

EXAMPLE 142B ethyl (2Z)-3-[4-(trifluoromethyl)phenyl]-2-butenoate

The title compound was isolated from the chromatography described inExample 142A. (Z) isomer: ¹H NMR (300 MHz, d₆-DMSO) 7.71 (d, 2H), 7.42(d, 2H), 6.03 (m, 1H), 3.90 (q, 2H), 2.18 (d, 3H), 1.00 (t, 3H); MS(DCI/NH₃) m/e 259 (M+H)⁺.

EXAMPLE 142C (2E)-3-[4-(trifluoromethyl)phenyl]-2-butenoic acid

The product from Example 142A (3.5 g, 13.5 mmol) in EtOH (80 mL) wastreated with aqueous 1M NaOH (40 mL) and stirred for 16 hours at ambienttemperature. The reaction mixture was neutralized with 1N HCl (40 mL),diluted with brine, and extracted with diethyl ether to provide thetitle compound. NMR (CDCl₃) 2.60 (s, 3H), 6.82 (s, 1H), 7.58 (d, 2H),7.65 (d, 2H).

EXAMPLE 142D(2E)-N-5-isoquinolinyl-3-[4-(trifluoromethyl)phenyl]-2-butenamide

The product from Example 142C (0.23 g, 1.00 mmol) in CH2Cl₂ (5 mL) wastreated with oxalyl chloride (0.15 g, 1.2 mmol), 1 drop of DMF, andstirred at ambient temperature for 45 minutes. The mixture was treatedwith a solution of 5-aminoisoquinoline (0.14 g, 1.0 mmol) and 98% NaH(0.048 g, 1.2 mmol) in DMF (5 mL) prepared separately by stirring for 45minutes. The resulting mixture was stirred for 15 minutes, poured intowater, and extracted with CH₂Cl₂. The organic phase was dried (MgSO₄),evaporated, and the residue triturated with diethyl ether. The solid wasdried under reduced pressure to provide the title compound. ¹H NMR (300MHz, d₆-DMSO) 2.61 (s, 3H), 2.73 (s, 0.45H, DMF)), 2.89 (s, 0.45H(DMF)), 6.82 (br s, 1H), 7.70 (t, 1H), 7.83 (s, 4H), 7.95 (d, 1H), 8.04(d, 1H), 8.21 (d, 1H), 8.56 (d, 1H), 9.33 (s, 1H), 10.20 (s, 1H); MS(ESI+) 357 (M+H)⁺; Elemental: Calculated for C₂₀H₁₅N₂OF₃.HCl.0.15C₃H₇NO:C66.87, H4.40, N8.20; Found: C66.83, H4.20, N8.27.

EXAMPLE 143 N-5-isoquinolinyl-3-[4-(trifluoromethyl)phenyl]-3-butenamide

The title compound was isolated from the procedure described Example142D as a side-product. ¹H NMR (300 MHz, d₆-DMSO) 3.83 (s, 2H), 5.49 (s,1H), 5.74 (s, 1H), 7.64 (t, 1H), 7.77 (m, 4H), 793 (m, 2H), 8.49 (d,1H), 9.30 (s, 1H), 10.18 (s, 1H); MS (ESI+) 357 (M+H)⁺; Elemental:Calculated for C₂₀H₁₅N₂OF₃.0.6H₂O: C65.43, H4.45, N7.63; Found: C65.49,H4.08, N7.93.

EXAMPLE 144(2Z)-N-5-isoquinolinyl-3-[4-(trifluoromethyl)phenyl]-2-butenamideEXAMPLE 144A (2Z)-3-[4-(trifluoromethyl)phenyl]-2-butenoic acid

The title compound was prepared using the procedure described in Example142C using the product from Example 142B instead of the product fromExample 142A.

EXAMPLE 144B(2Z)-N-5-isoquinolinyl-3-[4-(trifluoromethyl)phenyl]-2-butenamide

The title compound was prepared using the procedure described in Example142D using the product from Example 144A instead of the product fromExample 142C. ¹H NMR (300 MHz, d₆-DMSO) 2.21 (s, 3H), 6.48 (s, 1H), 7.50(d, 2H), 7.60 (t, 1H), 7.67 (d, 2H), 7.90 (d, 1H), 7.95 (d, 1H), 8.44(d, 1H), 9.27 (s, 1H), 10.03 (s, 1H); MS (ESI+) 357 (M+H)⁺; Elemental:Calculated for C₂₀H₁₅N₂OF₃: C67.41, H4.24, N7.86; Found: C67.16, H4.15,N7.59.

EXAMPLE 145(2E)-3-[3-fluoro-4-(trifuoromethyl)phenyl]-N-5-isoquinolinyl-2-butenamideEXAMPLE 145A (2E)-3-[3-fluoro-4-(trifluoromethyl)phenyl]-2-butenoic acid

The title compound was prepared using1-[3-fluoro-4-(trifluoromethyl)phenyl]ethanone and the proceduresdescribed in Examples 142A and 142C.

EXAMPLE 145B (2E)-3-[3-fluoro-4-(trifluoromethyl)phenyl]-2-butenoic acid

The title compound was prepared using the procedure described in 142Dusing the product from Example 145A instead of the product from Example142C. ¹H NMR (300 MHz, d₆-DMSO) 2.59 (s, 3H), 6.92 (s, 1H), 7.68 (d,1H), 7.78 (d, 1H), 7.93 (m, 2H), 8.25 (d, 1H), 8.44 (d, 1H), 8.49 (d,1H), 8.70 (d, 1H), 9.76 (s, 1H), 10.59 (s, 1H); MS (ESI+) 375 (M+H)⁺;Elemental: Calculated for C₂₀H₁₄N₂OF₄.1.6HCl: C55.52, H3.63, N6.47;Found: C55.60, H3.80, N6.09.

EXAMPLE 1463-[3-fluoro-4-(trifluoromethyl)phenyl]-N-5-isoquinolinyl-3-butenamide

The title compound was isolated from the procedure described in Example145B as a side-product. ¹H NMR (300 MHz, d₆-DMSO) 3.88 (s, 2H), 5.57 (s,1H), 5.86 (s, 1H), 7.60-7.88 (m, 4H), 8.18 (m, 3H), 8.64 (d, 1H), 9.65(s, 1H), 10.50 (s, 1H); MS (ESI+) 375 (M+H)⁺; Elemental: Calculated forC₂₀H₁₄N₂OF₄.HCl.0.2NH₄Cl: C56.99, H3.78, N7.31; Found: C56.73, H3.69,N7.43.

768062 EXAMPLE 147(2E)-N-5-isoquinolinyl-3-[4-(1-piperidinyl)phenyl]-2-butenamide EXAMPLE147A (2E)-3-[4-(1-piperidinyl)phenyl]-2-butenoic acid

The title compound was prepared using 1-[4-1-piperidinyl)phenyl]ethanoneand the procedures described in Examples 142A and 142C.

EXAMPLE 147B(2E)-N-5-isoquinolinyl-3-[4-(1-piperidinyl)phenyl]-2-butenamide

The title compound was prepared using the procedure described in 142Dusing the product from Example 147A instead of the product from Example142C. ¹H NMR (300 MHz, d₆-DMSO) 10.50 (s, 1H), 9.82 (s, 1H), 8.71 (d,1H), 8.58 (d, 1H), 8.47 (d, 1H), 8.26 (d, 1H), 7.95 (m, 2H), 7.62 (m,2H), 6.80 (s, 1H), 3.20 (m, 4H), 2.58 (s, 3H), 1.90-1.56 (m, 6H); MS(DCI/NH₃) m/e 372 (M+H)⁺; Anal. Calcd. For C₂₄H₂₅N₃O. 2.0 HCl. 2.0 H₂O.0.3 DMF: C 59.24; H 6.69; N 9.27. Found: C 59.44; H 6.83; N 9.24.

EXAMPLE 148 N-(3-fluorobenzyl)-N′-(3-methyl-5-isoquinolinyl)urea

The title compound was prepared using the procedure described in Example60F using 1-fluoro-3-(isocyanatomethyl)benzene and3-methyl-5-isoquinolinamine instead of the product from Example 60E and1-bromo-4-(isocyanatomethyl)benzene. ¹H NMR (300 MHz, DMSO-d₆) δ 9.18(s, 1H), 8.69 (bs, 1H), 8.87 (bs, 1H), 8.20 (d, 1H, J=6.9 Hz), 7.76 (s,1H), 7.70 (d, 1H, J=7.8 Hz), 7.50 (t, 1H, J=7.8 Hz), 7.41 (m, 1H),7.23-7.05 (m, 3H), 4.39 (d, 2H, J=6 Hz), 2.65 (s, 3H). MS (ESI) 310(M+H)⁺. Anal. Calcd for C₁₈H₁₆FN₃O: C, 69.89; H, 5.21; N, 13.58. Found:C, 69.86; H, 5.24; N, 13.56.

EXAMPLE 149 N-(4-bromo-3-fluorobenzyl)-N′-5-isoquinolinylurea

The title compound was prepared using the procedure described in Example1B using 4-bromo-3-fluorobenzylamine instead of2-(3-fluorophenyl)ethylamine. ¹H NMR (300 MHz, DMSO-d₆) δ 9.74 (s, 1H),9.55 (s, 1H), 8.67 (m, 2H), 8.57 (dd, 1H, J=7.8, 1.5 Hz), 8.06 (d, 1H,J=7.8 Hz), 7.88 (t, 1H, J=7.8 Hz), 7.67 (m, 2H), 7.35 (dd, 1H, J=9.6,2.4 Hz), 7.17 (dd, 1H, J=8.7, 1.8 Hz), 4.39 (d, 2H, J=6.3 Hz). MS (ESI)374/376 (M+H)⁺. Anal. Calcd for C₁₇H₁₃BrFN₃O.HCl: C, 49.72; H, 3.44; N,10.23. Found: C, 50.04; H, 3.50; N, 10.25

EXAMPLE 150 N-(3-amino-5-isoquinolinyl)-N′-[4-(1-piperidinyl)benzyl]ureaEXAMPLE 150A N-(3-amino-5-isoquinolinyl)-2,2,2-trichloroacetamide

The title compound was prepared using the procedure described in Example1A using 3,5-isoquinolinediamine instead of 5-aminoisoquinoline.

EXAMPLE 150BN-(3-amino-5-isoquinolinyl)-N′-[4-(1-piperidinyl)benzyl]urea

The title compound was prepared using the procedure described in Example1B using 4-(1-piperidinyl)benzylamine and the product from Example 150Ainstead of 2-(3-fluorophenyl)ethylamine and the product from Example 1A.¹H NMR (300 MHz, DMSO-d₆) δ 8.77 (s, 1H), 8.22 (s, 1H), 7.87 (d, 1H, J=8Hz), 7.46 (d, 1H, J=8 Hz), 7.16 (d, 2H, J=8.4 Hz), 7.07 (t, 1H, J=8 Hz),6.91 (d, 2H, J=8.4 Hz), 6.82 (t, 1H, J=6 Hz), 6.70 (s, 1H), 5.91 (s,2H), 4.22 (d, 2H, J=6 Hz), 3.10 (m, 4H), 1.70-1.45 (m, 6H). MS (ESI) 376(M+H)⁺. Anal. Calcd for C₂₂H₂₅N₅O.0.1H₂O: C, 70.04; H, 6.73; N, 18.56.Found: C, 69.66; H, 6.50; N, 18.55.

EXAMPLE 151 N-(3-amino-5-isoquinolin yl)-N′-[4-(1-azepanyl)benzyl]urea

The title compound was prepared using the procedure described in Example1B using 4-(1-azepanyl)benzylamine and the product from Example 150Ainstead of 2-(3-fluorophenyl)ethylamine and the product from Example 1A.¹H NMR (300 MHz, DMSO-d₆) δ 8.77 (s, 1H), 8.19 (s, 1H), 7.88 (d, 1H,J=8.7 Hz), 7.45 (d, 1H, J=8.7 Hz), 7.09 (m, 3H), 6.76 (t, 1H, J=5.4 Hz),6.66 (m, 3H), 5.90 (s, 2H), 4.17 (d, 2H, J=5.4 Hz), 3.24 (m, 4H), 1.71(m, 4H), 1.44 (m, 4H); MS (ESI) 390 (M+H)⁺; Anal. Calcd forC₂₃H₂₇N₅O.0.4H₂O: C, 69.64; H, 7.06; N, 17.65. Found: C, 69.53; H, 6.81;N, 17.38.

EXAMPLE 152 N-(1,1′-biphenyl-3-ylmethyl)-N′-5-isoquinolinylurea

The title compound was prepared using the procedure described in Example61B using 1,1′-biphenyl-3-ylmethylamine instead of 4-cyanobenzylalcohol. ¹H NMR (300 MHz, DMSO-d₆) δ 9.73 (s, 1H), 9.47 (s, 1H), 8.64(m, 3H), 8.05 (d, 1H, J=9 Hz), 7.87 (t, 1H, J=9 Hz), 7.68 (m, 3H), 7.58(m, 2H), 7.47 (m, 3H), 7.37 (m, 2H), 4.48 (d, 2H, J=6 Hz); MS (ESI) 354(M+H)⁺. Anal. Calcd for C₂₃H₁₉N₃O.HCl: C, 70.86; H, 5.17; N, 10.78.Found: C, 70.77; H, 5.16; N, 10.74.

EXAMPLE 153 N-5-isoquinolinyl-N′-[4-(2-pyridinyl)benzyl]urea

The title compound was prepared using the procedure described in Example61B using 4-(2-pyridinyl)benzylamine instead of 4-cyanobenzyl alcohol.¹H NMR (300 MHz, DMSO-d₆) δ 9.83 (s, 1H), 9.81 (s, 1H), 8.88 (d, 1H,J=6.3 Hz), 8.72 (m, 3H), 8.10 (m, 5H), 7.92 (m, 2H), 7.56 (m, 3H), 4.49(d, 2H, J=5.4 Hz); MS (ESI) 355 (M+H)⁺; Anal. Calcd forC₂₂H₁₈N₄O.1.8HCl: C, 62.91; H, 4.75; N, 13.34. Found: C, 62.95; H, 4.99;N, 13.27

EXAMPLE 154 N-(4-bromo-3-fluorobenzyl)-N′-(3-methyl-5-isoquinolinyl)urea

EXAMPLE 154A 5-isocyanato-3-methylisoquinoline

The title compound was prepared using the procedure described in Example61A using 3-methyl-5-isoquinolinamine instead of 5-aminoisoquinoline.

EXAMPLE 154BN-(4-bromo-3-fluorobenzyl)-N′-(3-methyl-5-isoquinolinyl)urea

The title compound was prepared using the procedure described in Example61B using 4-bromo-3-fluorobenzylamine and the product from Example 154Ainstead of 4-cyanobenzyl alcohol and the product from Example 61A. ¹HNMR (300 MHz, DMSO-d₆) δ 9.68 (s, 1H), 9.46 (s, 1H), 8.51 (m, 2H), 8.01(d, 1H, J=7.8 Hz), 7.80 (t, 1H, J=7.8 Hz), 7.67 (m, 2H), 7.36 (dd, 1H,J=9, 1.5 Hz), 7.18 (dd, 1H, J=9, 1 Hz), 4.39 (d, 2H, J=6 Hz), 2.77 (s,3H); MS (ESI) 388/390 (M+H)⁺; Anal. Calcd for C₁₈H₁₅BrFN₃O.HCl: C,50.91; H, 3.80; N, 9.89. Found: C, 50.81; H, 3.74; N, 9.87

EXAMPLE 155N-[3-fluoro-4-(4-methyl-1-piperidinyl)benzyl]-N′-(3-methyl-5-isoquinolinyl)urea

The title compound was prepared using the procedure described in Example61B using 3-fluoro-4-(4-methyl-1-piperidinyl)benzylamine and the productfrom Example 154A instead of 4-cyanobenzyl alcohol and the product fromExample 61A. ¹H NMR (300 MHz, DMSO-d₆) δ 9.74 (s, 1H), 9.52 (s, 1H),8.66 (s, 1H), 8.59 (d, 1H, J=8.4 Hz), 8.04 (d, 1H, J=8.4 Hz), 7.83 (t,1H, J=8.4 Hz), 7.62 (t, 1H, J=6 Hz), 7.10 (m, 3H), 4.32 (d, 2H, J=6 Hz),3.31 (m, 2H), 2.79 (s, 3H), 2.69 (m, 2H), 1.71 (m, 2H), 1.49 (m, 1H),1.32 (m, 2H), 0.95 (d, 3H, J=6 Hz). MS (ESI) 407 (M+H)⁺; Anal. Calcd forC₂₄H₂₇FN₄O.2.3HCl: C, 58.79; H, 6.02; N, 11.43. Found: C, 58.73; H,6.18; N, 11.19.

EXAMPLE 156N-(3-methyl-5-isoquinolinyl)-N′-[4-(4-methyl-1-piperidinyl)benzyl]urea

The title compound was prepared using the procedure described in Example61B using 4-(4-methyl-1-piperidinyl)benzylamine and the product fromExample 154A instead of 4-cyanobenzyl alcohol and the product fromExample 61A. ¹H NMR (300 MHz, DMSO-d₆) δ 9.70 (s, 1H), 9.66 (s, 1H),8.74 (s, 1H), 8.59 (d, 1H, J=8.7 Hz), 8.01 (d, 1H, J=8.7 Hz), 7.82 (m,2H), 7.65 (m, 2H), 7.48 (m, 2H), 4.40 (d, 2H, J=6Hz), 3.54 (m, 4H), 2.78(s, 3H), 1.90-1.50 (m, 5H), 0.98 (d, 3H, J=6 Hz); MS (ESI) 389 (M+H)⁺;Anal. Calcd for C₂₄H₂₈N₄O.2.6HCl: C, 59.64; H, 6.38; N, 11.59. Found: C,59.31; H, 6.39; N, 11.19.

EXAMPLE 157N-[3-fluoro-4-(1-piperidinyl)benzyl]-N′-(3-methyl-5-isoquinolinyl)urea

The title compound was prepared using the procedure described in Example61B using 3-fluoro-4-(1-piperidinyl)benzylamine and the product fromExample 154A instead of 4-cyanobenzyl alcohol and the product fromExample 61A. ¹H NMR (300 MHz, DMSO-d₆) δ 9.73 (s, 1H), 9.47 (s, 1H),8.62 (s, 1H), 8.58 (d, 1H, J=8.4 Hz), 8.04 (d, 1H, J=8.4 Hz), 7.83 (t,1H, J=8.4 Hz), 7.57 (t, 1H), 7.10 (m, 3H), 4.32 (d, 2H, J=6 Hz), 2.98(m, 4H), 2.79 (s, 3H), 1.67 (m, 4H), 1.53 (m, 2H); MS (ESI) 393 (M+H)⁺;Anal. Calcd for C₂₃H₂₅FN₄O.1.5HCl: C, 61.78; H, 5.97; N, 12.53. Found:C, 61.40; H, 6.04; N, 12.18.

EXAMPLE 158N-(3-methyl-5-isoquinolinyl)-N′-[4-(1-piperidinyl)benzyl]urea

The title compound was prepared using the procedure described in Example61B using 4-(1-piperidinyl)benzylamine and the product from Example 154Ainstead of 4-cyanobenzyl alcohol and the product from Example 61A. ¹HNMR (300 MHz, DMSO-d₆) δ 9.69 (s, 1H), 9.60 (s, 1H), 8.68 (s, 1H), 8.57(d, 1H, J=7.5 Hz), 8.00 (d, 1H, J=7.5 Hz), 7.85 7.55 (m, 4H), 7.43 (m,2H), 4.40 (d, 2H, J=6 Hz), 3.44 (m, 4H), 2.77 (s, 3H), 1.90 (m, 4H),1.65 (m, 2H); MS (ESI) 375 (M+H)⁺; Anal. Calcd for C₂₃H₂₆N₄O.2.4HCl: C,59.80; H, 6.20; N, 12.13. Found: C, 59.91; H, 6.45; N, 11.78

EXAMPLE 159 N-[4-(1-azepanyl)benzyl]-N′-(3-methyl-5-isoquinolinyl)urea

The title compound was prepared using the procedure described in Example61B using 4-(1-azepanyl)benzylamine and the product from Example 154Ainstead of 4-cyanobenzyl alcohol and the product from Example 61A. ¹HNMR (300 MHz, DMSO-d₆) δ 9.16 (s, 1H), 8.53 (s, 1H), 8.28 (d, 1H, J=8Hz), 7.74 (s, 1H), 7.67 (d, 1H, J=8 Hz), 7.50 (t, 1H, J=8 Hz), 7.14 (d,2H, J=9 Hz), 6.84 (t, 1H, J=6 Hz), 6.66 (d, 2H, J=9 Hz), 4.20 (d, 2H,J=6 Hz), 3.44 (m, 4H), 2.63 (s, 3H), 1.71 (m, 4H), 1.45 (m, 4H). MS(ESI) 389 (M+H)⁺; Anal. Calcd for C₂₄H₂₈N₄O.0.3H₂O: C, 73.18; H, 7.32;N, 14.22. Found: C, 73.08; H, 7.38; N, 14.22.

EXAMPLE 160N-(3-methyl-5-isoquinolinyl)-N′-[4-(1-pyrrolidinyl)benzyl]urea

The title compound was prepared using the procedure described in Example61B using 4-(1-pyrrolidinyl)benzylamine and the product from Example154A instead of 4-cyanobenzyl alcohol and the product from Example 61A.¹H NMR (300 MHz, DMSO-d₆) δ 9.15 (s, 1H), 8.54 (s, 1H), 8.27 (d, 1H,J=7.5 Hz), 7.73 (s, 1H), 7.67 (d, 1H, J=7.5 Hz), 7.49 (t, 1H, J=7.5 Hz),7.16 (d, 2H, J=9 Hz), 6.84 (t, 1H, J=6 Hz), 6.53 (d, 2H, J=9 Hz), 4.22(d, 2H, J=6 Hz), 3.20 (m, 4H), 2.63 (s, 3H), 1.94 (m, 4H); MS (ESI) 361(M+H)⁺. Anal. Calcd for C₂₂H₂₄N₄O.0.2H₂O: C, 72.58; H, 6.76; N, 15.39.Found: C, 72.33; H, 6.64; N, 15.22.

EXAMPLE 161N-[3-fluoro-4-(1-pyrrolidinyl)benzyl]-N′-(3-methyl-5-isoquinolinyl)urea

The title compound was prepared using the procedure described in Example61B using 3-fluoro-4-(1-pyrrolidinyl)benzylamine and the product fromExample 154A instead of 4-cyanobenzyl alcohol and the product fromExample 61A. ¹H NMR (300 MHz, DMSO-d₆) δ 9.17 (s, 1H), 8.59 (s, 1H),8.22 (d, 1H, J=7.5 Hz), 7.73 (s, 1H), 7.69 (d, 1H, J=7.5 Hz), 7.50 (t,1H, J=7.5 Hz), 7.03 (m, 2H), 6.93 (t, 1H, J=6 Hz), 6.72 (m, 1H), 4.24(d, 2H, J=6 Hz), 3.28 (m, 4H), 2.64 (s, 3H), 1.88 (m, 4H); MS (ESI) 379(M+H)⁺; Anal. Calcd for C₂₂H₂₃FN₄O: C, 69.82; H, 6.13; N, 14.80. Found:C, 69.76; H, 6.06; N, 14.69.

EXAMPLE 162N-[4-(1-azepanyl)-3-fluorobenzyl]-N′-(3-methyl-5-isoquinolinyl)urea

The title compound was prepared using the procedure described in Example61B using 4-(1-azepanyl)-3-fluorobenzylamine and the product fromExample 154A instead of 4-cyanobenzyl alcohol and the product fromExample 61A. ¹H NMR (300 MHz, DMSO-d₆) δ 9.74 (s, 1H), 8.50 (s, 1H),8.67 (s, 1H), 8.60 (d, 1H, J=8.1 Hz), 8.14 (d, 1H, J=8.1 Hz), 7.83 (t,1H, J=8.1 Hz), 7.56 (t, 1H), 7.04 (m, 2H), 6.90 (m, 1H), 4.26 (d, 2H,J=6 Hz), 3.32 (m, 4H), 2.79 (s, 3H), 1.75 (m, 4H), 1.55 (m, 4H); MS(ESI) 407 (M+H)⁺; Anal. Calcd for C₂₄H₂₇FN₄O.2HCl: C, 60.13; H, 6.10; N,11.69. Found: C, 60.09; H, 6.35; N, 11.47.

EXAMPLE 163 N-[4-(1-azocanyl)benzyl]-N′-(3-methyl-5-isoquinolinyl)urea

The title compound was prepared using the procedure described in Example61B using 4-(1-azocanyl)benzylamine and the product from Example 154Ainstead of 4-cyanobenzyl alcohol and the product from Example 61A. ¹HNMR (300 MHz, DMSO-d₆) δ 9.15 (s, 1H), 8.53 (s, 1H), 8.27 (d, 1H, J=7.5Hz), 7.73 (s, 1H), 7.67 (d, 1H, J=7.5 Hz), 7.50 (t, 1H, J=7.5 Hz), 7.15(m, 2H), 6.83 (t, 1H, J=5.4 Hz), 6.63 (m, 2H), 4.20 (d, 2H, J=5.4 Hz),3.43 (m, 4H), 2.63 (s, 3H), 1.67 (m, 4H), 1.48 (m, 6H); MS (ESI) 403(M+H)⁺; Anal. Calcd for C₂₅H₃₀N₄O: C, 74.60; H, 7.51; N, 13.92. Found:C, 74.26; H, 7.48; N, 13.64.

EXAMPLE 164N-[4-(1-azocanyl)-3-fluorobenzyl]-N′-(3-methyl-5-isoquinolinyl)urea

The title compound was prepared using the procedure described in Example61B using 4-(1-azocanyl)-3-fluorobenzylamine and the product fromExample 154A instead of 4-cyanobenzyl alcohol and the product fromExample 61A. ¹H NMR (300 MHz, DMSO-d₆) δ 9.70 (s, 1H), 9.37 (s, 1H),8.56 (m, 2H), 8.01 (d, 1H, J=8.4 Hz), 7.81 (t, 1H, J=8.4 Hz), 7.45 (t,1H), 7.02 (m, 2H), 6.90 (m, 1H), 4.25 (d, 2H, J=6 Hz), 3.35 (m, 4H),2.77 (s, 3H), 1.67 (m, 4H), 1.54 (m, 6H); MS (ESI) 421 (M+H)⁺; Anal.Calcd for C₂₅H₂₉FN₄O.HCl: C, 65.71; H, 6.62; N, 12.26. Found: C, 65.44;H, 6.49; N, 12.15.

EXAMPLE 165N-[(1S)-1-(4-bromophenyl)ethyl]-N′-(3-methyl-5-isoquinolinyl)urea

The title compound was prepared using the procedure described in Example61B using (1S)-1-(4-bromophenyl)ethanamine and the product from Example154A instead of 4-cyanobenzyl alcohol and the product from Example 61A.

EXAMPLE 166N-{(1S)-1-[4-(1-azepanyl)phenyl]ethyl}-N′-(3-methyl-5-isoquinolinyl)urea

The product from Example 165 (568 mg, 1.48 mmol, hexamethyleneimine (834μL, 7.39 mmol), Pd₂dba₃ (271 mg, 0.30 mmol), BINAP (460 mg, 0.74 mmol),and sodium tert-butoxide (1.42 g, 14.8 mmol) were combined in1,4-dioxane (20 mL) and heated to reflux. After 16 hours, the reactionwas cooled to ambient temperature and concentrated in vacuo. The residuewas purified by flash chromatography (1% to 5% CH₃OH/CH₂Cl₂) to providethe title compound. ¹H NMR (300 MHz, DMSO-d₆) δ 9.15 (s, 1H), 8.48 (s,1H), 8.28 (d 1H, J=8.4 Hz), 7.72 (s, 1H), 7.64 (d, 1H, J=8.4 Hz), 7.47(t, 1H, J=8.4 Hz), 7.16 (m, 2H), 6.90 (d, 1H, J=7.5 Hz), 6.66 (m, 2H),4.74 (m, 1H), 3.43 (m, 4H), 2.64 (s, 3H), 1.71 (m, 4H), 1.44 (m, 7H). MS(ESI) 403 (M+H)⁺. Anal. Calcd for C₂₅H₃₀N₄O.0.2CH₃OH: C, 74.01; H, 7.59;N, 13.70. Found: C, 74.39; H, 7.60; N, 13.32.

EXAMPLE 167 N-benzyl-N′-(3-chloro-5-isoquinolinyl)urea

The product from Example 60E (250 mg, 1.4 mmol) and1-bromo-4-(isocyanatomethyl)benzene (0.22 mL, 1.57 mmol) were heated intoluene (5 mL) at 80° C. for 3 hours. The mixture was cooled to roomtemperature and the precipitated solid was collected by filtration,washed with toluene, and air-dried to provide the title compound. ¹H NMR(300 MHz, DMSO-d₆) δ 9.18 (s, 1H), 8.81 (s, 1H), 8.32 (dd, J=7.8 Hz, 0.7Hz, 1H), 8.09 (s, 1H), 7.80 (d, J=8.2 Hz, 1H), 7.53-7.65 (m, 3H), 7.32(m, 2H), 7.05 (t, J=5.7 Hz, 1H), 4.35 (d, J=5.7 Hz, 2H); MS (ESI⁺) m/z391/393 (M+H, ³⁵Cl/³⁷Cl).

EXAMPLE 168 N-(4-bromobenzyl)-N′-(1-chloro-5-isoquinolinyl)urea EXAMPLE168A 1-chloro-5-isoquinolinamine

The title compound was prepared using the procedures described inExamples 60D and 60E using 1-chloroisoquinoline instead of the productfrom Example 60C.

EXAMPLE 168B N-(4-bromobenzyl)-N′-(1-chloro-5-isoquinolinyl)urea

The title compound was prepared using the procedure described in Example60F using the product from Example 168A instead of the product fromExample 60E. ¹H NMR (300 MHz, DMSO-d₆) δ 8.89 (s, 1H), 8.34-8.37 (m,2H), 8.00 (dd, J=6.1 Hz, 0.7 Hz, 1H), 7.92-7.95 (m, 1H), 7.73 (t, J=8.1,1H), 7.53-7.56 (m, 2H), 7.30-7.33 (m, 2H), 7.12 (t, J=5.8 Hz, 1H), 4.35(d, J=5.8 Hz, 2H); MS (ESI⁺) m/z 390/392 (M+H, ³⁵Cl/³⁷Cl).

EXAMPLE 169 N-(4-cyanobenzyl)-N′-5-isoquinolinylurea EXAMPLE 169A4-(aminomethyl)benzonitrile

A solution of N,N-bis(tert-butoxycarbonyl)-4-cyanobenzylamine (0.75 g,2.25 mmol, prepared according to the literature described in SyntheticCommunications 4419:28 (1998), in CH₂Cl₂ (15 mL) was treated withtrifluoroacetic acid (8 mL). After stirring at room temperature for 3hours, the mixuture was concentrated under reduced pressure and theresidue was azeotroped with diethyl ether.

EXAMPLE 169B N-(4-cyanobenzyl)-N′-5-isoquinolinylurea

The title compound was prepared using the procedure described in Example61B using the product from Example 169A instead of 4-cyanobenzylalcohol. Purification was by chromatography (95:5 CH₂Cl₂:MeOH) toprovide the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ 9.75 (s, 1H),9.62 (s, 1H), 8.69 (s, 2H), 8.58 (dd, J=7.8 Hz, 1.0 Hz, 1H), 8.07 (d,J=7.4 Hz, 1H), 7.90 (d, J=8.1 Hz, 1H), 7.81-7.85 (m, 2H), 7.74 (t, J=6.1Hz, 1H), 7.54-7.57 (m, 2H), 4.48 (d, J=6.1 Hz, 2H); MS (ESI⁺) m/z 303(M+H)⁺.

EXAMPLE 170 N-(4-bromobenzyl)-N′-(3-methyl-5-isoquinolinyl)urea

The product from Example 63A (500 mg, 3.1 mmol) and1-bromo-4-(isocyanatomethyl)benzene (0.5 mL, 3.57 mmol) were stirred intoluene (10 mL) at 80° overnight. The mixture was cooled to roomtemperature, and the resulting precipitate was collected by filtration,washed with toluene, and allowed to air-dry. The correspondinghydrochloride salt was prepared using methanolic HCl to afford a tansolid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.70 (s, 1H), 9.54 (s, 1H), 8.63 (s,1H), 8.57 (dd, J=7.8 Hz, 1.0 Hz, 1H), 8.02 (d, J=8.2 Hz, 1H), 7.78-7.83(m, 1H), 7.67-7.71 (m, 1H), 7.52-7.57 (m, 2H), 7.30-7.35 (m, 2H), 4.36(d, J=5.7 Hz, 2H), 2.78 (s, 3H); MS (ESI⁺) m/z 370/372 (M+H,⁷⁹Br/⁸¹Br)⁺.

EXAMPLE 171 N-(4-bromobenzyl)-N′-(1-methyl-5-isoquinolinyl)urea EXAMPLE171A 1-methyl-5-isoquinolinamine

The title compound was prepared using the procedures described inExamples 60D and 60E using 1-methylisoquinoline instead of the productfrom Example 60C.

EXAMPLE 171B N-(4-bromobenzyl)-N′-(1-methyl-5-isoquinolinyl)urea

The product from Example 171A (480 mg, 3.04 mmol) and1-bromo-4-(isocyanatomethyl)benzene (0.43, 3.07 mmol) were stirred intoluene (9 mL) at 90° for 1 hour, then the mixture was cooled to roomtemperature. The precipitate was collected by filtration and washed withtoluene. The corresponding dihydrochloride salt was prepared usingmethanolic HCl. ¹H NMR (300 MHz, DMSO-d₆) δ 8.74 (s, 1H), 8.38 (d, J=6.1Hz, 1H), 8.25 (d, J=7.8 Hz, 1H), 7.78-7.85 (m, 2H), 7.53-7.61 (m, 3H),7.32 (d, J=8.5 Hz, 2H), 7.11 (t, J=6.1 Hz, 1H), 4.34 (d, J=6.1 Hz, 2H),2.88 (s, 3H); MS (ESI⁺) m/z 370/372 (M+H, ⁷⁹Br/⁸¹Br)⁺.

EXAMPLE 172 N-5-isoquinolinyl-N′-[4-(4-morpholinyl)benzyl]urea EXAMPLE172A 4-(4-morpholinyl)benzonitrile

4-Fluorobenzonitrile (1 g, 8.26 mmol) and morpholine (2.2 mL, 25.2 mmol)were stirred in DMSO (25 mL) at 100° C. for 2.5 hours, cooled to roomtemperature, poured into H₂O, and extracted with diethyl ether. Thecombined organic extracts were washed with H₂O and brine, dried overNa₂SO₄, and evaporated in vacuo to provide the title compound.

EXAMPLE 172B 4-(4-morpholinyl)benzylamine

4-(4-Morpholinyl)benzonitrile (1.24 g, 6.6 mmol) in THF (25 mL) at 0° C.was treated with LiAlH₄ (2.5 g, 65.9 mmol) and refluxed for 1 hour. Themixture was cooled to room temperature and quenched by careful additionof 1N NaOH and then H₂O. The mixture was concentrated, extracted withdiethyl ether. The combined ethereal extracts were washed with saturatedNaHCO₃ solution, dried over Na₂SO₄, and evaporated in vacuo to providethe title compound which was dried over MgSO₄ as a THF:diethylethersolution before the next step.

EXAMPLE 172C N-5-isoquinolinyl-N′-[4-(4-morpholinyl)benzyl]urea

The product from Example 172B (285 mg, 1.48 mmol) in diethyl ether (10mL) was treated with an ethereal solution of 5-isocyanatoisoquinoline,causing a white precipitate to form. This precipitate was collected byfiltration and purified by chromatography (95:5 CH₂Cl₂-MeOH, eluant) toprovide the title compound. The corresponding di-hydrochloride salt wasprepared using methanolic HCl to afford a yellow solid. ¹H NMR (300 MHz,DMSO-d₆) δ 9.26 (s, 1H), 8.67 (s, 1H), 8.52-8.55 (m, 1H), 8.32 (dd,J=7.8 Hz, 1.1 Hz, 1H), 7.92 (d, J=6.1 Hz, 1H), 7.73 (d, J=8.2 Hz, 1H),7.60 (m, 1H), 7.23 (d, J=8.8 Hz, 2H), 6.92-6.96 (m, 3H), 4.26 (d, 5.4Hz, 2H), 3.72-3.75 (m, 4H), 3.06-3.12 (m, 4H); MS (ESI⁺) m/z 363 (M+H)⁺.

EXAMPLE 173N-[4-(2,6-dimethyl-4-morpholinyl)benzyl]-N′-5-isoquinolinylurea EXAMPLE173A 4-(2,6-dimethyl-4-morpholinyl)benzylamine

The title compound was prepared using the procedures described inExamples 172A and 172B using 2,6-dimethylmorpholine instead ofmorpholine.

EXAMPLE 173BN-[4-(2,6-dimethyl-4-morpholinyl)benzyl]-N′-5-isoquinolinylurea

The title compound was prepared using the procedure described in Example172C using the product from Example 173A instead of the product fromExample 172B. ¹H NMR (300 MHz, DMSO-d₆) δ 9.26 (s, 1H), 8.67 (s, 1H),8.53 (d, J=6.1 Hz, 1H), 8.31 (dd, J=7.6 Hz, 1.1 Hz, 1H), 7.92 (d, J=6.1Hz, 1H), 7.73 (d, J=8.1 Hz, 1H), 7.57-7.62 (m, 1H), 7.22 (d, J=8.8 Hz,2H), 6.92-6.95 (m, 3H), 4.26 (d, J=5.7 Hz, 2H), 3.68 (m, 2H), 3.54-3.57(m, 2H), 2.21 (m, 2H), 1.16 (s, 3H), 1.14 (s, 3H); MS (ESI⁺) m/z 391(M+H).

EXAMPLE 174 N-5-isoquinolinyl-N′-[4-(4-thiomorpholinyl)benzyl]ureaEXAMPLE 174A 4-(4-thiomorpholinyl)benzylamine

The title compound was prepared using the procedures described inExamples 172A and 172B using thiomorpholine instead of morpholine.

EXAMPLE 174B N-5-isoquinolinyl-N′-[4-(4-thiomorpholinyl)benzyl]urea

The title compound was prepared using the procedure described in Example172C using the product from Example 174A instead of the product fromExample 172B. ¹H NMR (300 MHz, DMSO-d₆) δ 9.26 (s, 1H), 8.67 (s, 1H),8.53 (d, J=6.1 Hz, 1H), 8.32 (dd, J=7.8 Hz, 1.1 Hz, 1H), 7.92 (d, J=6.1Hz, 1H), 7.73 (d, J=8.2 Hz, 1H), 7.60 (m, 1H), 7.20-7.23 (m, 2H),6.90-6.96 (m, 3H), 4.25 (d, J=5.8 Hz, 2H), 3.45-3.51 (m, 4H), 2.64-2.67(m, 4H); MS (ESI⁺) m/z 379 (M+H).

EXAMPLE 175 N-(4-bromobenzyl)-N′-(3-fluoro-5-isoquinolinyl)urea EXAMPLE175A 3-fluoro-5-isoquinolinamine

The title compound was prepared using the procedures described inExamples 60D and 60E using 3-fluoroisoquinoline, prepared according tothe procedure described in J. Am. Chem. Soc., 687:73 (1951), instead ofthe product from Example 60C.

EXAMPLE 175B N-(4-bromobenzyl)-N′-(3-fluoro-5-isoquinolinyl)urea

The title compound was prepared using the procedure described in Example60F using the product from Example 175A instead of the product fromExample 60E. ¹H NMR (300 MHz, DMSO-d₆) δ 9.09 (s, 1H), 8.74 (s, 1H),8.28 (d, 1H, J=7.8 Hz), 7.83 (d, 1H, J=8.4 Hz), 7.66 (s, 1H), 7.55 (m,3H), 7.32 (d, 2H, J=8.5 Hz), 7.03 (t, 1H, J=5.9 Hz), 4.35 (d, 2H, J=6.1Hz); MS (ESI⁺) m/z 373/375 (M+H, ⁷⁹Br/⁸¹Br).

EXAMPLE 176N-(3-chloro-5-isoquinolinyl)-N′-[4-(4-morpholinyl)benzyl]urea EXAMPLE176A 3-chloro-5-isocyanatoisoquinoline

5-Amino-3-chloroisoquinoline (740 mg, 4.15 mmol) was suspended intoluene (20 mL) and treated with 20% w/v phosgene solution in toluene (9mL) and triethylamine (5 mL). The mixture was refluxed overnight and wasthen concentrated in vacuo and used in the next step without furtherpurification.

EXAMPLE 176BN-(3-chloro-5-isoquinolinyl)-N′-[4-(4-morpholinyl)benzyl]urea

The product from Example 176A in diethyl ether (40 mL) was treated withthe product from Example 172B (300 mg, 1.56 mmol) and triethylamine (3mL) in 1:1 diethyl ether:CH₃CN (10 mL). After stirring for 3 hours, themixture was filtered, and the collected solid was washed with diethylether. The solid was purified by silica gel chromatography (95:5CH₂Cl₂:MeOH) to provide the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ9.18 (s, 1H), 8.71 (s, 1H), 8.37 (d, 1H, J=6.7 Hz), 8.08 (s, 1H), 7.79(d, 2H, J=8.2 Hz), 7.63 (t, 1H), J=8.0 Hz), 7.23 (d, 2H, J=8.7 Hz), 6.94(d, 2H, J=8.4 Hz), 6.91 (t, 1H, 5.5 Hz), 4.26 (d, 2H, 5.7 Hz), 3.73 (m,4H), 3.07 (m, 4H); MS (ESI⁺) m/z 397/399 (M+H, ³⁵Cl/³⁷Cl).

EXAMPLE 177N-[3,5-difluoro-4-(4-morpholinyl)benzyl]-N′-5-isoquinolinylurea EXAMPLE177A 3,5-difluoro-4-(4-morpholinyl)benzylamine

The title compound was prepared using the procedures described inExamples 172A and 172B using 3,4,5-trifluorobenzonitrile instead of4-fluorobenzonitrile.

EXAMPLE 177BN-[3,5-difluoro-4-(4-morpholinyl)benzyl]-N′-5-isoquinolinylurea

The product from Example 177A (500 mg, 2.19 mmol) in diethyl ether (5mL) was treated with an ethereal solution of 5-isocyanatoisoquinoline.The resulting waxy precipitate was collected by filtration and air-driedto provide the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ 9.27 (s, 1H),8.79 (s, 1H), 8.54 (d, 1H, J=6.1 Hz), 8.26 (dd, 1H, J=7.8 Hz, 1.0 Hz),7.94 (d, 1H, 6.1 Hz), 7.76 (d, 1H, 8.2 Hz), 7.60 (t, 3H, J=7.6 Hz), 7.10(t, 1H, J=6.0 Hz), 7.03 (m, 2H), 4.31 (d, 2H), 3.68 (m, 4H), 3.07 (m,4H); MS (ESI⁺) m/z 399 (M+H).

EXAMPLE 178 N-(4-bromobenzyl)-N′-(1,3-dimethyl-5-isoquinolinyl)ureaEXAMPLE 178A 1,3-dimethyl-5-isoquinolinamine

The title compound was prepared using the procedures described inExamples 60D and 60E using 1,3-dimethylisoquinoline, prepared accordingto the procedure described in Helv. Chim. Acta 1627:75 (1992), insteadof the product from Example 60C.

EXAMPLE 178B N-(4-bromobenzyl)-N′-(1,3-dimethyl-5-isoquinolinyl)urea

The product from Example 178A(375 mg, 2.2 mmol) in toluene (7 mL) wastreated with 1-bromo-4-(isocyanatomethyl)benzene (0.31 mL, 2.2 mmol).After stirring at 85-90° C. for 3 hours, the mixture was cooled to roomtemperature and filtered. The filter cake was treated with methanolicHCl to provide the title compound as the hydrochloride salt. ¹H NMR (300MHz, DMSO-d₆) δ 8.62 (s, 1H), 8.17 (d, 1H, J=7.8 Hz), 7.80 (d, 1H, J=8.5Hz), 7.45-7.60 (m, 4H), 7.32 (d, 2H, J=8.1 Hz), 7.06 (t, 1H, 5.7 Hz),4.34 (d, 2H, 5.8 Hz), 2.84 (s, 3H), 2.75 (s, 3H); MS (ESI⁺) m/z 383/385(M+H, ⁷⁹Br/⁸¹Br).

EXAMPLE 179 N-(3,4-dimethylbenzyl)-N′-(3-methyl-5-isoquinolinyl)urea

3,4-Dimethylbenzylamine (0.3 mL, 2.1 mmol) in toluene (11 mL) was addedcarefully to a 20% w/v solution of phosgene in toluene (4.5 mL). Themixture was refluxed overnight and was then concentrated in vacuo. Theresidue was then taken up in toluene (10 mL) and treated with DIEA (1.5mL, 8.63 mmol) and 5-amino-3-methylisoquinoline (155 mg, 1.08 mmol). Thereaction mixture was stirred at 80° for 2 h and was then cooled to roomtemperature. The precipitated solid was collected by filtration and waschromatographed on silica gel (97:3 CH₂Cl₂—CH₃OH to 9:1 CH₂Cl₂—CH₃OH,eluant gradient) to afford the desired product, A-473191. Treatment ofthis solid with methanolic HCl yielded the corresponding hydrochloridesalt. ¹H NMR (300 MHz, DMSO-d₆) δ 9.16 (s, 1H), 8.59 (s, 1H), 8.24 (d,1H, J=7.8 Hz), 7.74 (s, 1H), 7.68 (d, 1H, J=8.2 Hz), 7.50 (t, 1H, J=7.9Hz), 7.08-7.12 (m, 3H), 6.95 (m, 1H), 4.28 (d, 2H, 5.8 Hz), 2.64 (s,3H), 2.22 (s, 3H), 2.20 (s, 3H); MS (ESI³⁰ ) m/z 320 (M+H).

EXAMPLE 180N-[3,5-bis(trifluoromethyl)benzyl]-N′-(3-methyl-5-isoquinolinyl)urea

The title compound was prepared using the procedure described in Example179 using 3,5-bis(trifluoromethyl)benzylamine instead of3,4-dimethylbenzylamine. ¹H NMR (300 MHz, DMSO-d₆) δ 9.18 (s, 1H), 8.79(s, 1H), 8.01-8.13 (m, 4H), 7.73 (m, 2H), 7.51 (t, 1H, J=8.0 Hz), 7.23(t, 1H, J=6.0 Hz), 4.55 (d, 2H, J=6.1 Hz), 2.64 (s, 3H); MS (ESI⁺) m/z428 (M+H).

EXAMPLE 181 N-(3-amino-5-isoquinolinyl)-N′-(4-bromobenzyl)urea EXAMPLE181A N-3-isoquinolinylacetamide

3-Aminoisoquinoline (495 mg, 3.44 mmol) was stirred in Ac₂O (9 mL) at60° for 16 hours. The mixture was cooled to room temperature andconcentrated in vacuo to provide the title compound which was used inthe next step without further purification.

EXAMPLE 181B 3,5-isoquinolinediamine

The title compound was prepared using the procedures described inExamples 60D and 60E using the product from Example 181A instead of theproduct from Example 60C.

EXAMPLE 181C N-(3-amino-5-isoquinolinyl)-N′-(4-bromobenzyl)urea

The title compound was prepared using the procedure described in Example179 using 4-bromobenzylamine and the product from Example 181B insteadof 3,4-dimethylbenzylamine and 5-amino-3-methylisoquinoline. Thecorresponding hydrochloride salt was formed by treatment of the freebase with methanolic HCl. ¹H NMR (300 MHz, DMSO-d₆) δ 8.78 (s, 1H), 8.33(s, 1H), 7.82 (d, 1H, J=7.5 Hz), 7.47-7.56 (m, 3H), 7.29 (d, 2H, J=8.1Hz), 7.08 (t, 1H, J=7.8 Hz), 6.99 (m, 1H), 6.71 (s, 1H), 5.94 (br s,2H), 4.31 (d, 2H, J=6.1 Hz); MS (ESI⁺) m/z 370/372 (M+H, ⁷⁹Br/⁸¹Br).

EXAMPLE 182N-(3-methyl-5-isoquinolinyl)-N′-[4-(trifluoromethyl)benzyl]urea

4-(Trifluoromethyl)benzylamine (1 mL, 7.02 mmol) in toluene (4 mL) wastreated with 20% w/v phosgene solution in toluene (5 mL), and the wholemixture was refluxed overnight. After this time, the mixture wasconcentrated in vacuo, then was taken up again in toluene (8 mL). Tothis was added 5-amino-3-methylisoquinoline (340 mg, 2.15 mmol) and DIEA(4 mL) in toluene (8 mL). The reaction was allowed to stir at 80° for 3h and then was cooled to room temperature. The precipitate was collectedby filtration and purified by chromatography on silica gel (97:3CH₂Cl₂—CH₃OH to 95:5 CH₂Cl₂—CH₃OH, eluant gradient) to afford A-638488as a white solid. Treatment with methanolic HCl yielded thecorresponding hydrochloride salt. ¹H NMR (300 MHz, DMSO-d₆) δ 9.18 (s,1H), 8.73 (s, 1H), 8.20 (d, 1H, J=7.3 Hz), 7.69-7.75 (m, 4H), 7.58 (d,2H, J=8.2 Hz), 7.50 (t, 1H, 7.8 Hz), 7.16 (t, 1H, J=5.9 Hz), 4.47 (d,2H, J=6.1 Hz), 2.65 (s, 3H); MS (ESI⁺) m/z 360 (M+H).

EXAMPLE 183 N-(4-tert-butylbenzyl)-N′-(3-methyl-5-isoquinolinyl)urea

The title compound was prepard using the procedure described in Example182 using 4-tert-butylbenzylamine instead of4-(trifluoromethyl)benzylamine. The corresponding hydrochloride salt wasobtained after treatment of the free base with methanolic HCl. ¹H NMR(300 MHz, DMSO-d₆) δ 9.16 (s, 1H), 8.60 (s, 1H), 8.24 (dd, 1H, J=7.8 Hz,1.1 Hz), 7.74 (s, 1H), 7.68 (d, 2H, J=8.2 Hz), 7.50 (t, 1H, J=7.9 Hz),7.38 (m, 2H), 7.29 (m, 2H), 6.99 (t, 1H, J=5.8 Hz), 4.32 (d, 2H, J=5.8Hz), 2.64 (s, 3H), 1.28 (s, 9H); MS (ESI⁺) m/z 348 (M+H).

EXAMPLE 184 N-(4-tert-butylbenzyl)-N′-(1,3-dimethyl-5-isoquinolinyl)ureaEXAMPLE 184A 1-(isocyanatomethyl)-4-(trifluoromethyl)benzene

The title compound was prepared using the procedure described in Example61A using 4-(trifluoromethyl)benzylamine instead of 5-aminoisoquinoline.

EXAMPLE 184BN-(4-tert-butylbenzyl)-N′-(1,3-dimethyl-5-isoquinolinyl)urea

The product from Example 184A (3.16 mmol) in toluene (12 mL) was treatedwith the product from Example 178A (273 mg, 1.59 mmol) and DIEA (5 mL).The mixture was heated at 80° for 3 hours before being cooled to roomtemperature and filtered. The precipitate thus obtained was purified bysilica gel chromatography (97:3 CH₂Cl₂—CH₃OH to 95:5 CH₂Cl₂—CH₃OH,eluant gradient) to provide the title compound. The correspondinghydrochloride salt was prepared by treatment with methanolic HCl. ¹H NMR(300 MHz, DMSO-d₆) δ 8.68 (s, 1H), 8.16 (d, 1H, J=7.5 Hz), 7.80 (d, 1H,J=8.1 Hz), 7.73 (d, 2H, J=8.2 Hz), 7.56-7.61 (m, 3H), 7.48 (t, 1H, J=8.1Hz), 7.15 (t, 1H, J=5.7 Hz), 4.46 (d, 2H, J=5.7 Hz), 2.84 (s, 3H), 2.58(s, 3H); MS (ESI⁺) m/z 374 (M+H).

EXAMPLE 185 4-(3-chlorophenyl)-N-5-isoquinolinyl-1-piperazinecarboxamide

1-(3-Chlorophenyl)piperazine (206 mg, 1.05 mmol) in diethyl ether (20mL) was treated with an ethereal solution of 5-isocyanatoisoquinoline.The precipitate that formed was collected by filtration, washed withdiethyl ether and air-dried to provide the title compound. ¹H NMR (300MHz, DMSO-d₆) δ 9.30 (s, 1H), 8.84 (s, 1H), 8.49 (d, 1H, J=7.1 Hz), 7.92(d, 1H, J=7.8 Hz), 7.78 (d, 1H, 6.8 Hz), 7.61-7.72 (m, 2H), 7.25 (t, 1H,J=8.1 Hz), 6.96-7.04 (m, 2H), 6.81-6.84 (m, 1H), 3.68 (m, 4H), 3.29 (m,4H); MS (ESI⁺) m/z 367 (M+H).

EXAMPLE 186 N-(4-tert-butylbenzyl)-N′-(1,3-dimethyl-5-isoquinolinyl)ureaEXAMPLE 186A 1-tert-butyl-4-(isocyanatomethyl)benzene

The title compound was prepared using the procedure described in Example61A using 4-tert-butylbenzylamine instead of 5-aminoisoquinoline.

EXAMPLE 186BN-(4-tert-butylbenzyl)-N′-(1,3-dimethyl-5-isoquinolinyl)urea

The product from Example 186A (3.42 mmol) in toluene (12 mL) was treatedwith 5-amino-1,3-dimethylisoquinoline (245 mg, 1.42 mmol) and DIEA (5mL). The mixture was heated at 80° for 3 hours, cooled to roomtempoerature, and filtered. The precipitate thus obtained was purifiedby silica gel chromatography (97:3 CH₂Cl₂:CH₃OH to 95:5 CH₂Cl₂:CH₃OH) toprovide the title compound. The corresponding hydrochloride salt wasprepared by treatment with methanolic HCl. ¹H NMR (300 MHz, DMSO-d₆) δ8.55 (s, 1H), 8.21 (d, 1H, J=7.1 Hz), 7.78 (d, 1H, 8.5 Hz), 7.59 (s,1H), 7.48 (t, 1H, J=8.0 Hz), 7.36-7.40 (m, 2H), 7.27-7.29 (m, 2H), 6.98(m, 1H), 4.31 (d, 2H, J=5.8 Hz), 2.84 (s, 3H), 1.28 (s, 9H); MS (ESI⁺)m/z 362 (M+H).

EXAMPLE 1874-(3,4-dimethylphenyl)-N-5-isoquinolinyl-1-piperazinecarboxamide

1-(3,4-Dimethylphenyl)piperazine (194 mg, 1.02 mmol) in diethyl ether(20 mL) was treated with an ethereal solution of5-isocyanatoisoquinoline. The precipitate that formed was collected byfiltration, washed with diethyl ether, and air-dried to provide thetitle compound. ¹H NMR (300 MHz, DMSO-d₆) δ 9.29 (d, 1H, J=0.7 Hz), 8.82(s, 1H), 8.49 (d, J=6.2 Hz, 1H), 7.90-7.93 (m, 1H), 7.76-7.79 (m, 1H),7.61-7.71 (m, 2H), 7.00 (d, 1H, 8.5 Hz), 6.83 (d, 1H, J=2.4 Hz), 6.73(dd, 1H, J=83 Hz, 2.5 Hz), 3.67 (m, 4H), 3.15 (m, 4H), 2.19 (s, 3H),2.13 (s, 3H); MS (ESI⁺) m/z 361 (M+H).

EXAMPLE 188 4-(4-chlorophenyl)-N-5-isoquinolinyl-1-piperazinecarboxamide

1-(4-Chlorophenyl)piperazine (197 mg, 1.01 mmol) in diethyl ether (20mL) was treated with an ethereal solution of 5-isocyanatoisoquinoline.The precipitate that formed was collected by filtration, washed withdiethyl ether, and air-dried to provide the title compound. ¹H NMR (300MHz, DMSO-d₆) δ 9.29 (d, 1H, J=1.0 Hz), 8.83 (s, 1H), 8.49 (d, 1H, 6.1Hz), 7.93 (d, 1H, J=7.8 Hz), 7.77 (m, 1H), 7.61-7.72 (m, 2H), 7.26-7.29(m, 2H), 7.01-7.04 (m, 2H), 3.68 (m, 4H), 3.23 (m, 4H); MS (ESI⁺) m/z367 (M+H).

EXAMPLE 189N-5-isoquinolinyl-3-methyl-4-(4-methylphenyl)-1-piperazinecarboxamide

The title compound was prepared using the procedure described in Example188 using 2-methyl-1-(4-methylphenyl)piperazine instead of1-(4-chlorophenyl)piperazine. ¹H NMR (300 MHz, DMSO-d₆) δ 9.29 (d, 1H,J=0.6 Hz), 8.77 (d, 1H, J=5.1 Hz), 8.49 (d, 1H, J=5.7 Hz), 7.92 (d, 1H,7.5 Hz), 7.61-7.77 (m, 3H), 7.06 (d, 2H, 8.2 Hz), 6.86-6.91 (m, 2H),3.61 and 4.53 (2m, 1H), 4.09 (m, 1H), 3.93 (m, 1H), 3.49 (m, 1H), 3.39(m, 1H), 2.62-3.24 (m, 2H), 2.22 (s, 3H), 1.35 and 0.98 (2d, 3H, J=6.4and 6.1 Hz); MS (ESI⁺) m/z 361 (M+H).

EXAMPLE 1904-(2,3-dimethylphenyl)-N-5-isoquinolinyl-1-piperazinecarboxamide

The title compound was prepared using the procedure described in Example188 using 1-(2,3-dimethylphenyl)piperazine instead of1-(4-chlorophenyl)piperazine. ¹H NMR (300 MHz, DMSO-d₆) δ 9.29 (d, 1H,J=1.0 Hz), 8.80 (s, 1H), 8.50 (d, 1H, J=5.7 Hz), 7.92 (d, 1H, J=8.2 Hz),7.79 (dd, 1H, J=6.1 Hz, 1.0 Hz), 7.61-7.73 (m, 2H) 7.07 (m, 1H0,6.90-6.96 (m, 2H), 3.70 (m, 4H), 2.87 (m, 4H), 2.23 (s, 3H), 2.23 (s,3H); MS (ESI⁺) m/z 361 (M+H).

EXAMPLE 1914-(2,3-dichlorophenyl)-N-5-isoquinolinyl-1-piperazinecarboxamide

The title compound was prepared using the procedure described in Example188 using 1-(2,3-dichlorophenyl)piperazine instead of1-(4-chlorophenyl)piperazine. ¹H NMR (300 MHz, DMSO-d₆) δ 9.30 (d, 1H,J=0.7 Hz), 8.83 (s, 1H), 8.50 (d, 1H, J=5.8 Hz), 7.92 (d, 1H, J=7.8 Hz),7.79 (dd, 1H, J=5.1 Hz, 1.0 Hz), 7.62-7.73 (m, 2H), 7.33-7.36 (m, 2H),7.21-7.24 (m, 1H), 3.71 (m, 4H), 3.07 (m, 4H); MS (ESI⁺) m/z 401/403(M+H, ³⁵Cl/³⁷Cl).

EXAMPLE 192N-[3-fluoro-4-(trifluoromethyl)benzyl]-N′-(3-methyl-5-isoquinolinyl)ureaEXAMPLE 192A 2-fluoro-4-(isocyanatomethyl)-1-(trifluoromethyl)benzene

The title compound was prepared using the procedure described in Example61A using 3-fluoro-4-(trifluoromethyl)benzylamine instead of5-aminoisoquinoline.

EXAMPLE 192BN-[3-fluoro-4-(trifluoromethyl)benzyl]-N′-(3-methyl-5-isoquinolinyl)urea

The product from Example 192A (4.4 mmol) in toluene (10 mL) was treatedwith 5-amino-3-methylisoquinoline (460 mg, 2.9 mmol) and DIEA (3 mL).The mixture was heated at 80° for 1.5 hours, cooled to room temperature,and filtered. The precipitate thus obtained was purified by silica gelchromatography (97:3 CH₂Cl₂:CH₃OH to 95:5 CH₂Cl₂:CH₃OH) to provide thetitle compound. The corresponding hydrochloride salt was prepared bytreatment with methanolic HCl. ¹H NMR (300 MHz, DMSO-d₆) δ 9.18 (s, 1H),8.77 (s, 1H), 8.17 (dd, 1H, J=7.8 Hz, 1.0 Hz), 7.70-7.81 (m, 3H),7.38-7.53 (m, 3H), 7.19 (t, 1H, 6.1 Hz), 4.47 (d, 2H, J=5.8 Hz), 2.65(s, 3H); MS (ESI⁺) m/z 378 (M+H).

EXAMPLE 193 N-[1-(4-bromophenyl)ethyl]-N′-(3-methyl-5-isoquinolinyl)ureaEXAMPLE 193A 1-bromo-4-(1-isocyanatoethyl)benzene

The title compound was prepared using the procedure described in Example61A using 1-(4-bromophenyl)ethylamine instead of 5-aminoisoquinoline.

EXAMPLE 193BN-[1-(4-bromophenyl)ethyl]-N′-(3-methyl-5-isoquinolinyl)urea

The title compound was prepared using the procedure described in Example192B using the product from Example 193A instead of the product fromExample 192A. The corresponding hydrochloride salt was prepared bytreatment with methanolic HCl. ¹H NMR (300 MHz, DMSO-d₆) δ 9.16 (s, 1H),8.56 (s, 1H), 8.20 (dd, 1H, J=7.8 Hz, 1.0 Hz), 7.72 (s, 1H), 7.67 (d,1H, J=8.2 Hz), 7.56 (m, 2H), 7.47 (t, 1H, J=7.8 Hz), 7.35 (m, 2H), 7.12(d, 1H, J=7.4 Hz), 4.85 (m, 1H), 2.65 (s, 3H), 1.43 (d, 3H, J=7.1 Hz);MS (ESI⁺) m/z 384/386 (M+H, ⁷⁹Br/⁸¹Br).

EXAMPLE 194 N-(3,4-dichlorobenzyl)-N′-(3-methyl-5-isoquinolinyl)ureaEXAMPLE 194A 1,2-dichloro-4-(isocyanatomethyl)benzene

The title compound was prepared using the procedure described in Example61A using 3,4-dichlorobenzylamine instead of 5-aminoisoquinoline.

EXAMPLE 194B N-(3,4-dichlorobenzyl)-N′-(3-methyl-5-isoquinolinyl)urea

5-Amino-3-methylisoquinoline (390 mg, 2.47 mmol) and the product fromExample 194A (0.36 mL, 2.45 mmol) were heated in toluene (10 mL) at 80°for 2.5 hours. Upon cooling to room temperature, a precipitate formed,which was collected by filtration, washed with toluene, and air-dried.Remaining impurities were removed by slurrying the solid in 9:1CH₂Cl₂:CH₃OH and then filtering the mixture to provide the titlecompound. The corresponding hydrochloride salt was formed by treatmentof the free base with methanolic HCl. ¹H NMR (300 MHz, DMSO-d₆) δ 9.17(s, 1H), 8.27 (s, 1H), 8.17 (dd, 1H, J=7.8 Hz, 1.0 Hz), 7.74 (s, 1H),7.71 (d, 1H, J=8.1 Hz), 7.61 (m, 2H), 7.50 (t, 1H, J=8.0 Hz), 7.35 (dd,1H, J=8.3 Hz, 2.2 Hz), 7.12 (t, 1H, 5.9 Hz), 4.37 (d, 2H, J=6.1 Hz),2.65 (s, 3H); MS (ESI⁺) m/z 360/362 (M+H, ³⁵Cl/³⁷Cl).

EXAMPLE 195 N-(2,4-dichlorobenzyl)-N′-(3-methyl-5-isoquinolinyl)ureaEXAMPLE 195A 2,4-dichloro-1-(isocyanatomethyl)benzene

The title compound was prepared using the procedure described in Example61A using 2,4-dichlorobenzylamine instead of 5-aminoisoquinoline.

EXAMPLE 195B N-(2,4-dichlorobenzyl)-N′-(3-methyl-5-isoquinolinyl)urea

5-Amino-3-methylisoquinoline (390 mg, 2.47 mmol) and the product fromExample 195A (0.36 mL, 2.47 mmol) were heated in toluene (10 mL) at 80°for 2.5 hours. Upon cooling to room temperature, a precipitate formed,which was collected by filtration, washed with toluene, and air-dried.Remaining impurities were removed by slurrying the solid in 9:1CH₂Cl₂:CH₃OH and then filtering the mixture to provide the titlecompound. The corresponding hydrochloride salt was formed by treatmentof the free base with methanolic HCl. ¹H NMR (300 MHz, DMSO-d₆) δ 9.17(s, 1H), 8.78 (s, 1H), 8.21 (dd, 1H, J=7.4 Hz, 1.0 Hz), 7.77 (s, 1H),7.70 (d, 1H, J=8.1 Hz), 7.64 (m, 1H), 7.44-7.52 (m, 3H), 7.14 (t, 1H,J=6.1 Hz), 4.38 (d, 2H, J=6.0 Hz), 2.65 (s, 3H); MS (ESI⁺) m/z 360/362(M+H, ³⁵Cl/³⁷ Cl).

EXAMPLE 196 N-(3-chlorobenzyl)-N′-(3-methyl-5-isoquinolinyl)urea

3-chlorobenzylamine (141 mg, 1.0 mmol) in ether (20 mL) was treated withan ethereal solution of 5-isocyanato-3-methylisoquinoline. Theprecipitate that formed was collected by filtration, washed with diethylether, and air-dried to provide the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ 9.18 (s, 1H), 8.69 (s, 1H), 8.20 (d, 1H, J=7.8 Hz), 7.75 (s,1H), 7.70 (d, 1H, J=8.2 Hz), 7.51 (t, 1H, J=7.8 Hz), 7.31-7.43 (m, 4H),7.10 (m, 1H), 4.38 (d, 2H, J=5.7 Hz), 2.65 (s, 3H); MS (ESI⁺) m/z326/328 (M+H, ³⁵Cl/³⁷Cl).

EXAMPLE 197N-(3-methyl-5-isoquinolinyl)-N′-[4-(trifluoromethoxy)benzyl]urea

The title compound was prepared using the procedure described in Example196 using 4-(trifluoromethoxy)benzylamine instead of3-chlorobenzylamine. ¹H NMR (300 MHz, DMSO-d₆) δ 9.17 (s, 1H), 8.68 (s,1H), 8.21 (d, 1H, J=7.8 Hz), 7.75 (s, 1H), 7.70 (d, 1H, J=8.1 Hz),7.46-7.53 (m, 3H), 7.35-7.37 (m, 2H), 7.10 (t, 1H, 5.9 Hz), 4.40 (d, 2H,J=5.7 Hz), 2.64 (s, 3H); MS (ESI⁺) m/z 376 (M+H).

EXAMPLE 198N-[2-(3,4-dichlorophenyl)ethyl]-N′-(3-methyl-5-isoquinolinyl)urea

The title compound was prepared using the procedure described in Example196 using 2-(3,4-dichlorophenyl)ethylamine instead of3-chlorobenzylamine. ¹H NMR (300 MHz, DMSO-d₆) δ 9.16 (s, 1H), 8.54 (s,1H), 8.17 (d, 1H, J=7.5 Hz), 7.67-7.70 (m, 2H), 7.57-7.60 (m, 2H), 7.49(t, 1H, 7.8 Hz), 7.29 (dd, 1H, J=8.1 Hz, 2.0 Hz), 6.57 (t, 1H, J=5.7Hz), 3.43 (m, 2H), 2.82 (m, 2H), 2.64 (s, 3H); MS (ESI⁺) m/z 374/376(M+H, ³⁵Cl/³⁷Cl).

EXAMPLE 199 N-(4-ethylbenzyl)-N′-(3-methyl-5-isoquinolinyl)urea

The title compound was prepared using the procedure described in Example196 using 4-ethylbenzylamine instead of 3-chlorobenzylamine. ¹H NMR (300MHz, DMSO-d₆) δ 9.17 (s, 1H), 8.61 (s, 1H), 8.24 (d, 1H, J=7.8 Hz), 7.74(s, 1H), 7.68 (d, 1H, J=7.8 Hz), 7.50 (t, 1H, J=7.8 Hz), 7.19-7.29 (m,4H), 6.99 (m, 1H), 4.32 (d, 2H, J=5.7 Hz), 2.64 (s, 3H), 2.59 (q, 2H,J=7.6 Hz), 1.17 (t, 3H, J=7.6 Hz); MS (ESI⁺) m/z 320 (M+H).

EXAMPLE 200N-(3-methyl-5-isoquinolinyl)-N′-{2-[4-(trifluoromethyl)phenyl]ethyl}urea

The title compound was prepared using the procedure described in Example196 using 2-[4-(trifluoromethyl)phenyl]ethylamine instead of3-chlorobenzylamine. ¹H NMR (300 MHz, DMSO-d₆) δ 9.16 (s, 1H), 8.55 (s,1H), 8.20 (d, 1H, J=7.8 Hz), 7.67-7.70 (m, 4H), 7.46-7.53 (m, 3H), 6.60(t, 1H, J=5.6 Hz), 3.46 (m, 2H), 2.91 (m, 2H), 2.64 (s, 3H); MS (ESI⁺)m/z 374 (M+H).

EXAMPLE 201N-(3-methyl-5-isoquinolinyl)-N′-{4-[(trifluoromethyl)thio]benzyl}urea

The title compound was prepared using the procedure described in Example196 using 4-[(trifluoromethyl)thio]benzylamine instead of3-chlorobenzylamine. ¹H NMR (300 MHz, DMSO-d₆) δ 9.18 (s, 1H), 8.72 (s,1H), 8.21 (d, 1H, J=7.8 Hz), 7.69-7.76 (m, 4H), 7.50-7.53 (m, 3H), 7.15(m, 1H), 4.44 (d, 2H, J=6.1 Hz), 2.65 (s, 3H); MS (ESI⁺) m/z 392 (M+H).

EXAMPLE 202 N-(4-chlorobenzyl)-N′-(3-methyl-5-isoquinolinyl)urea

The title compound was prepared using the procedure described in Example196 using 4-chlorobenzylamine instead of 3-chlorobenzylamine. ¹H NMR(300 MHz, DMSO-d₆) δ 9.17 (s, 1H), 8.67 (s, 1H), 8.21 (m, 1H), 7.66-7.74(m, 2H), 7.37-7.53 (m, 5H), 7.08 (m, 1H), 4.36 (d, 2H, J=5.8 Hz), 2.64(s, 3H); MS (ESI⁺) m/z 326/328 (M+H, ³⁵Cl/³⁷Cl).

EXAMPLE 2034-(3,4-dichlorophenyl)-N-(3-methyl-5-isoquinolinyl)-1-piperazinecarboxamide

The title compound was prepared using the procedure described in Example196 using 1-(3,4-dichlorophenyl)piperazine instead of3-chlorobenzylamine. ¹H NMR (300 MHz, DMSO-d₆) δ 9.20 (s, 1H), 8.74 (s,1H), 7.86 (d, 1H, J=8.1 Hz), 7.51-7.66 (m, 3H), 7.43 (d, 1H, J=8.8 Hz),7.22 (d, 1H, J=3.1 Hz), 7.01 (dd, 1H, J=9.1 Hz, 3.1 Hz), 3.67 (m, 4H),3.28 (m, 4H), 2.62 (s, 3H); MS (ESI⁺) m/z 415/417 (M+H, ³⁵Cl/³⁷Cl).

EXAMPLE 204 N-(2,4-difluorobenzyl)-N′-(3-methyl-5-isoquinolinyl)urea

The title compound was prepared using the procedure described in Example196 using 2,4-difluorobenzylamine instead of 3-chlorobenzylamine. ¹H NMR(300 MHz, DMSO-d₆) δ 9.17 (s, 1H), 8.67 (s, 1H), 8.21 (dd, 1H, J7.5 Hz,1.0 Hz), 7.74 (s, 1H), 7.70 (d, 1H, J=8.1 Hz), 7.47-7.52 (m, 2H),7.05-7.29 (m, 3H), 4.38 (d, 2H, J=5.7 Hz), 2.64 (s, 3H); MS (ESI⁺) m/z328 (M+H).

EXAMPLE 205N-(1,3-dimethyl-5-isoquinolinyl)-N′-[3-fluoro-4-(trifluoromethyl)benzyl]ureaEXAMPLE 205A 2-fluoro-4-(isocyanatomethyl)-1-(trifluoromethyl)benzene

The title compound was prepared using the procedure described in Example61A using 3-fluoro-4-(trifluoromethyl)benzylamine instead of5-aminoisoquinoline.

EXAMPLE 205BN-(1,3-dimethyl-5-isoquinolinyl)-N′-[3-fluoro-4-(trifluoromethyl)benzyl]urea

The product from Example 205A (4.4 mmol) in toluene (10 mL) was treatedwith 1,3-dimethyl-5-isoquinolinamine (375 mg, 2.18 mmol) and DIEA (3.5mL) The mixture was heated at 80° overnight. After cooling to roomtemperature, the precipitated solids were collected by filtration andchromatographed on silica gel (98:2 CH₂Cl₂:CH₃OH to 95:5 CH₂Cl₂:CH₃OH)to provide the title compound. The corresponding hydrochloride salt wasprepared by treatment with methanolic HCl. ¹H NMR (300 MHz, DMSO-d₆) δ8.72 (s, 1H), 8.13 (d, 1H, J=7.8 Hz), 7.75-7.83 (m, 2H), 7.61 (s, 1H),7.38-7.51 (m, 3H), 7.18 (t, 1H, J=6.1 Hz), 4.46 (d, 2H, J=5.8 Hz), 2.84(s, 3H), 2.59 (s, 3H); MS (ESI⁺) m/z 392 (M+H).

EXAMPLE 206N-5-isoquinolinyl-4-[3-(trifluoromethyl)phenyl]-1-piperazinecarboxamide

The title compound was prepared using the procedure described in Example188 using 1-[3-(trifluoromethyl)phenyl]piperazine instead of1-(4-chlorophenyl)piperazine. ¹H NMR (300 MHz, DMSO-d₆) δ 9.30 (d, 1H,J=1.0 Hz), 8.85 (s, 1H), 8.49 (d, 1H, J=5.7 Hz), 7.12 (d, 1H, J=7.7 Hz),7.78 (m, 1H), 7.61-7.72 (m, 2H), 7.46 (m, 1H), 7.26-7.31 (m, 2H), 7.12(d, 1H, J=7.5 Hz), 3.70 (m, 4H), 3.35 (m, 4H); MS (ESI⁺) m/z 401 (M+H).

EXAMPLE 207 4-(4-bromophenyl)-N-5-isoquinolinyl-1-piperazinecarboxamide

The title compound was prepared using the procedure described in Example188 using 1-(4-bromophenyl)piperazine instead of1-(4-chlorophenyl)piperazine. The precipitate that formed was collectedby filtration, washed with diethyl ether, and air-dried. Purification bysilica gel chromatography provided the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ 9.29 (d, 1H, J=1.0 Hz), 8.83 (s, 1H), 8.49 (d, 1H, J=6.1 Hz),7.92 (d, 1H, J=7.8 Hz), 7.77 (m, 1H), 7.61-7.71 (m, 2H), 7.37-7.40 (m,2H), 6.96-6.99 (m, 2H), 3.68 (m, 4H), 3.23 (m, 4H); MS (ESI⁺) m/z411/413 (M+H, ⁷⁹Br/⁸¹Br).

EXAMPLE 208 N-(4-isopropylbenzyl)-N′-(3-methyl-5-isoquinolinyl)urea

4-Isopropylbenzylamine (748 mg, 5.02 mmol) in toluene (20 mL) wasrefluxed with 20% w/v phosgene solution in toluene (3 mL) overnight. Themixture was cooled to room temperature and concentrated in vacuo. Theresidue was taken up in toluene (20 mL) and was treated with DIEA (4 mL)and 5-amino-3-methylisoquinoline (500 mg, 3.16 mmol). The reactionmixture was stirred was at 80° C. for 6 hours. After cooling to roomtemperature, a precipitate formed which was collected by filtration andpurified by silica gel chromatography (98:2 CH₂Cl₂:CH₃OH) to provide thetitle compound. The corresponding hydrochloride salt was formed bytreatment with methanolic HCl. ¹H NMR (300 MHz, DMSO-d₆) δ 9.16 (s, 1H),8.60 (s, 1H), 8.24 (dd, 1H, J=7.5 Hz, 1.0 Hz), 7.74 (s, 1H), 7.68 (d,1H, J=8.2 Hz), 7.50 (t, 1H, J=8.0 Hz), 7.22-7.30 (m, 4H), 6.99 (t, 1H,5.6 Hz), 4.32 (d, 2H, J=7.8 Hz), 2.88 (m, 1H), 2.64 (s, 3H), 1.20 (d,6H, J=6.8 Hz); MS (ESI⁺) m/z 334 (M+H).

EXAMPLE 209N-[4-fluoro-3-(trifluoromethyl)benzyl]-N′-(3-methyl-5-isoquinolinyl)urea

4-Fluoro-3-(trifluoromethyl)benzylamine (0.8 g, 4.15 mmol) in toluene(20 mL) was refluxed with 20% w/v phosgene solution in toluene (2.1 mL)overnight. The mixture was cooled to room temperature and concentratedin vacuo. The residue was again taken up in toluene (25 mL) and wasstirred overnight at 80° C. with DIEA (2 mL, 11.5 mmol) and5-amino-3-methylisoquinoline (500 mg, 3.16 mmol). The mixture was cooledto room temperature, concentrated in vacuo, and the residue was purifiedby silica gel chromatography (97:3 CH₂Cl₂:CH₃OH, eluant) to provide thetitle compound. The corresponding hydrochloride salt was prepared bytreatment with methanolic HCl. ¹H NMR (300 MHz, DMSO-d₆) δ 9.18 (s, 1H),8.72 (s, 1H), 8.16 (d, 1H, J=7.8 Hz), 7.70-7.77 (m, 4H), 7.48-7.54 (m,3H), 7.14 (t, 1H, J=5.9 Hz), 4.42 (d, 2H, J=6.1 Hz), 2.64 (s, 3H); MS(ESI⁺) m/z 378 (M+H).

EXAMPLE 210N-(3-amino-5-isoquinolinyl)-N′-{1-[4-(trifluoromethyl)phenyl]ethyl}urea

1-(1-Isocyanatoethyl)-4-(trifluoromethyl)benzene (1.64 mmol) in toluene(8 mL) was treated with N-(5-amino-3-isoquinolinyl)acetamide (220 mg,1.09 mmol) and DIEA (1.4 mL). The mixture was heated at 80° C. for 6hours, cooled to room temperature, and the precipitate was collected byfiltration. The solid was triturated with 97:3 CH₂Cl₂:CH₃OH and stirredas a suspension in 48% aqueous HBr (8 mL) at 60° C. for 4 hours. Aftercooling to room temperature, the mixture was poured into concentratedNH₄OH (20 mL) and filtered. The solid was washed with water andair-dried to provide the title compound. The corresponding hydrochloridesalt was prepared by treatment with methanolic HCl. ¹H NMR (300 MHz,DMSO-d₆) δ 9.05 (s, 1H), 8.64 (s, 1H), 7.91 (d, 1H), 7.58-7.74 (m, 4H),7.22-7.36 (m, 3H), 7.14-7.18 (m, 2H), 6.97 (s, 1H), 4.94 (m, 1H), 1.44(d, 3H, J=6.8 Hz); MS (ESI⁺) m/z 375 (M+H).

EXAMPLE 211N-(3-amino-5-isoquinolinyl)-N′-[3-fluoro-4-(trifluoromethyl)benzyl]urea

2-Fluoro-4-(isocyanatomethyl)-1-(trifluoromethyl)benzene (2.59 mmol) intoluene (10 mL) was treated with N-(5-amino-3-isoquinolinyl)acetamide(400 mg, 1.99 mmol) and DIEA (1.8 mL). The mixture was heated at 80° C.for 5 hours, cooled to room temperature, and filtered. The solid wastriturated with 97:3 CH₂Cl₂:CH₃OH and stirred as a suspension in 48%aqueous HBr (8 mL) at 60° C. for 2 hours. After cooling to roomtemperature, the mixture was poured into concentrated NH₄OH (20 mL). Thesolid was washed with water and air-dried to provide the title compound.The corresponding hydrochloride salt was prepared by treatment withmethanolic HCl. ¹H NMR (300 MHz, DMSO-d₆) δ 8.81 (s, 1H), 8.68 (s, 1H),7.94 (s, 1H), 7.76 (t, 1H, J=7.9 Hz), 7.35-7.49 (m, 3H), 7.26 (s, 1H),7.09 (s, 1H), 6.92 (s, 1H), 6.84 (t, 1H, J=6.0 Hz), 6.62 (s, 1H), 4.41(d, 2H, J=6.1 Hz).

EXAMPLE 212 N-[(2,4-dichlorobenzyl)oxy]-N′-5-isoquinolinylurea

The title compound was prepared using the procedure described in Example61B using O-(2,5-dichlorobenzyl)hydroxylamine instead of 4-cyanobenzylalcohol. MS (ESI) m/z: 361.96 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 5.03 (s, 2H),7.52 (dd, 1H), 7.69 (m, 4H), 7.88 (d, 1H), 7.93 (d, 1H), 8.52 (d, 1H),9.00 (s, 1H), 9.31 (s, 1H), 9.77 (s, 1H).

EXAMPLE 213 N-(5-bromo-2-fluorobenzyl)-N′-5-isoquinolinylurea

The title compound was prepared using the procedure described in Example61B using 5-bromo-2-fluorobenzylamine instead of 4-cyanobenzyl alcohol.MS (ESI) m/z: 373.93 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 4.42 (d, 2H), 7.22 (t,1H), 7.54 (m, 2H), 7.60 (dd, 1H), 7.86 (t, 1H), 8.05 (d, 1H), 8.56 (t,2H), 8.69 (d, 1H), 9.45 (s, 1H), 9.72 (s, 1H).

EXAMPLE 214 N-(4-chloro-2-fluorobenzyl)-N′-5-isoquinolinylurea

The title compound was prepared using the procedure described in Example61B using 4-chloro-2-fluorobenzylamine instead of 4-cyanobenzyl alcohol.MS (ESI) m/z: 329.99 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 4.41 (d, 2H), 7.31 (dd,1H), 7.47 (m, 3H), 7.85 (t, 1H), 8.04 (d, 1H), 8.56 (d, 2H), 8.68 (d,1H), 9.42 (s, 1H), 9.71 (s, 1H).

EXAMPLE 215 2-(4-chlorophenyl)ethyl 5-isoquinolinylcarbamate

The title compound was prepared using the procedure described in Example61B using 2-(4-chlorophenyl)ethanol instead of 4-cyanobenzyl alcohol. MS(ESI) m/z: 327.04 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 2.99 (t, 2H), 4.37 (t, 2H),7.36 (q, 4H), 7.89 (t, 1H), 8.12 (d, 1H), 8.20 (d, 1H), 8.30 (d, 1H),8.63 (d, 1H), 9.72 (s, 1H), 9.97 (s, 1H).

EXAMPLE 216 2-[2-(trifluoromethyl)phenyl]ethyl 5-isoquinolinylcarbamate

The title compound was prepared using the procedure described in Example61B using 2-[2-(trifluoromethyl)phenyl]ethanol instead of 4-cyanobenzylalcohol. MS (ESI) m/z: 361.06 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 3.18 (t, 2H),4.42 (t, 2H), 7.48 (t, 1H), 7.63 (m, 2H), 7.72 (d, 1H), 7.90 (t, 1H),8.13 (d, 1H), 8.20 (d, 1H), 8.30 (d, 1H), 8.63 (d, 1H), 9.72 (s, 1H),10.01 (s, 1H).

EXAMPLE 217 N-(4-tert-butylbenzyl)-N′-5-isoquinolinylurea

The title compound was prepared using the procedure described in Example61B using 4(-tert-butyl)benzylamine instead of 4-cyanobenzyl alcohol. MS(ESI) m/z: 333 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.27 (s, 9H), 2.80 (t, 2H),2.95 (t, 2H), 7.22 (d, 2H), 7.33 (d, 2H), 7.67 (t, 1H), 7.80 (d, 1H),7.96 (t, 2H), 8.48 (d, 1H), 9.33 (s, 1H), 9.99 (s, 1H).

EXAMPLE 218 N-[(4-tert-butylcyclohexyl)methyl]-N′-5-isoquinolinylurea

The title compound was prepared using the procedure described in Example61B using (4-tert-butylcyclohexyl)methylamine instead of 4-cyanobenzylalcohol. MS (ESI) m/z: 340.18 (M+H)+; ¹H NMR (DMSO-d₆) δ 0.82 (d, 9H),0.93 (d, 4H), 1.09-1.50 (m, 2H), 1.74 (d, 2H), 1.82 (d, 2H), 3.01 & 3.19(t & dd, 2H), 7.19 & 7.24 (t & t, 1H), 7.87 (t, 1H), 8.03 (d, 1H), 8.63(dd, 1H), 8.67 (d, 1H), 8.76 (dd, 1H), 9.47 (d, 1H), 9.74 (s, 1H).

EXAMPLE 219 N-(3,4-difluorobenzyl)-N′-5-isoquinolinylurea

The title compound was prepared using the procedure described in Example61B using 3,4-difluorobenzylamine instead of 4-cyanobenzyl alcohol. MS(ESI) m/z: 314.07 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 4.36 (d, 2H), 7.12 (t, 1H),7.20 (m, 1H), 7.40 (t, 2H), 7.60 (t, 1H), 7.75 (d, 1H), 7.94 (d, 1H),8.26 (dd, 1H), 8.54 (d, 1H), 8.79 (s, 1H), 9.27 (s, 1H).

EXAMPLE 220N-5-isoquinolinyl-N′-{[4-(trifluoromethyl)cyclohexyl]methyl}urea

The title compound was prepared using the procedure described in Example61B using [4-(trifluoromethyl)cyclohexyl]methylamine instead of4-cyanobenzyl alcohol. MS (ESI) m/z: 352.07 (M+H)⁺; ¹H NMR (CDCl₃) δ1.05 & 1.27 (q & q, 1H), 1.58 (m, 2H), 1.66 (m, 2H), 1.70 (m, 2H), 1.94(m, 2H), 2.08 (m, 1H), 3.21 & 3.34 (d & d, 2H), 7.16 (br, 1H), 7.84 (s,2H), 8.35 (s, 1H), 8.82 (d, 1H), 9.12 (d, 1H), 9.36 (s, 1H), 9.49 (s,1H).

EXAMPLE 221 ethyl 5-isoquinolinylacetate

5-Bromoisquinoline (7.19 g, 34.5 mmol) in toluene (80 mL) was treatedwith dichlorobis(tri-o-tolylphosphine)palladium(II) (5 mol %, 1.3639 g,1.7 mmol) and tributylstannanylacetic acid ethyl ester in toluene (20mL). This mixture was heated at 125° C. overnight, cooled, diluted withethyl acetate (100 mL), washed with water (2×50 mL), dried (MgSO₄), andthe filtrate was concentrated under reduced pressure. The residue waspruified by column chromatography (20% ethyl acetate in hexanes to 50%ethyl acetate in hexanes) to provide the title compound. MS (ESI+) m/z216 (M+H)⁺, (ESI−) m/z 214 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 1.17 (t, J7.1, 3H), 4.09 (q, J 7.1, 2H), 4.17 (s, 2H), 7.64 (m, 1H), 7.72 (d, J6.2, 1H), 7.81 (d, J 5.7, 1H), 8.07 (d, J 7.9, 1H), 8.54 (d, J 6.1, 1H),9.33 (s, 1H); Anal. Calcd for C₁₃H₁₃NO₂0.6H₂O: C, 69.07; H, 6.33; N,6.2. Found: C, 59.4; H, 6.09; N, 5.89.

EXAMPLE 222 2-(5-isoquinolinyl)-N-[4-(trifluoromethoxy)benzyl]acetamideEXAMPLE 222A 5-isoquinolinylacetic acid

Ethyl 5-isoquinolinylacetate (1.15 g, 5.34 mmol) was dissolved inconcentrated H₂SO₄ (12 mL) and heated at 100° C. for 2 hours. Thereaction mixture was poured into ice (20 g) and the pH was adjusted to 6with 50% NaOH/H₂O. The mixture was allowed to set of several hours,filtered, and the filter cake was rinsed with water to provide the titlecompound. MS (ESI+) m/z 188 (M+H)⁺; ¹H NMR (DMSO, 300 MHz) δ 4.07 (s,2H), 7.67 (m, 2H), 7.83 (d, J 5.7, 1H), 8.05 (d, J 8.1, 1H), 8.53 (d, J6.1, 1H), 9.32 (s, 1H), 12.50 (s, 1H); ¹³C NMR (DMSO, 75 MHz) δ 37.6(CH₂CO), 117.1 (CH, C4), 126.8, 127.0 (CH, C7 & C8), 128.4 (C), 131.1(C), 132.0 (CH, C6), 134.4 (C), 143.0 (CH, C3), 152.7 (CH, C1),172.3(CO); Anal. Calcd for C₁₁H₉NO₂: C, 70.58; H, 4.85; N, 7.48. Found:C, 70.42; H, 4.93; N, 7.34.

EXAMPLE 222B 2-(5-isoquinolinyl)-N-[4-(trifluoromethoxy)benzyl]acetamide

Polymer supported 1,3-dicyclohexylcarbodiimide (0.845 g) indichloromethane (5 mL) was treated with 5-isoquinolinylacetic acid(0.075 g, 0.40 mmol) in dichloromethane (1 mL),1-hydroxy-7-azabenzotriazole (0.049 g), and triethylamine (0.080 g) indichloromethane (1 mL). After stirring for 5 minutes, the mixture wastreated with 4-(trifluoromethoxy)benzylamine (0.40 mmol). After stirringfor 16 hours, the mixture was treated with MP-Carbonate resin (0.310 g),stirred for 5 minutes, and filtered. The filtrate was diluted withdichloromethane (40 mL), washed with water (4×20 mL), brine (1×20 mL),dried (Na₅SO₄), filtered, and the filtrate was concentrated underreduced pressure to provide the title compound which was purified byforming the hydrochloride salt and triturating the solid with hot ethylacetate. MS (ESI+) m/z 361 (M+H)⁺; MS (ESI−) m/z 359 (M−H)⁻; ¹H NMR(DMSO, 300 MHz) δ 3.99 (s, 2H), 4.31 (d, J 5.7, 2H), 7.31 (d, J 8.8,2H), 7.36 (d, J 6.4, 2H), 7.66 (m, 2H), 7.93 (d, J 6.1, 1H), 8.03 (d, J8.2, 1H), 8.51 (d, J 6.1, 1H), 8.74 (t, J 6.1, 1H), 9.31 (s, 1H); Anal.Calcd for C₁₉H₁₅F₃N₂O₂+1 HCl: C, 57.51; H, 4.06; N, 7.06. Found: C,57.42; H, 3.98; N, 6.72.

EXAMPLE 223 N-(4-tert-butylbenzyl)-2-(5-isoquinolinyl)acetamide

The title compound was prepared using the procedure described in Example222B using 4-(tert-butyl)benzylamine instead of4-(trifluoromethoxy)benzylamine. MS (ESI+) m/z 333 (M+H)⁺; MS (ESI−) m/z331 (M−H⁻; ¹H NMR (DMSO, 300 MHz) δ 1.26 (s, 9H), 3.96 (s, 2H), 4.24 (d,J 6.1, 2H), 7.17 (d, J 8.5, 2H), 7.32 (d, J 6.4, 2H), 7.66 (m, 2H), 7.83(d, J 6.1, 1H), 8.03 (d, J 8.1, 1H), 8.51 (d, J 6.1, 1H), 8.65 (t, J5.8, 1H), 9.30 (s, 1H); Anal. Calcd for C₂₂H₂₄N₂O+1.15 HCl: C, 70.58; H,6.77; N, 7.48. Found: C, 70.56; H, 6.80; N, 7.39.

EXAMPLE 224N-[3-fluoro-4-(trifluoromethyl)benzyl]-2-(5-isoquinolinyl)acetamide

The title compound was prepared using the procedure described in Example222B using 3-fluoro-4-(trifluoromethyl)benzylamine instead of4-(trifluoromethoxy)benzylamine. MS (ESI+) m/z 363 (M+H)⁺; MS (ESI−) m/z361 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 4.21 (s, 2H), 4.38 (d, J 6.1, 2H),7.32 (m, 2H), 7.73 (t, J 7.8, 1H), 7.98 (t, J 8.1, 1H), 8.13 (d, J 7.1,1H), 8.44 (d, J 8.4, 1H), 8.72 (d, J 6.8, 1H), 9.07 (t, J 6.1, 1H), 9.88(s, 1H); Anal. Calcd for C₁₉H₁₄F₄N₂O+1.15 HCl: C, 56.45; H, 3.78; N,6.93. Found: C, 56.57; H, 3.69; N, 6.88.

EXAMPLE 225N-{1-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl}-2-(5-isoquinolinyl)acetamide

The title compound was prepared using the procedure described in Example222B using 1-[3-fluoro-4-(trifluoromethyl)phenyl]ethylamine instead of4-(trifluoromethoxy)benzylamine. MS (ESI+) m/z 377 (M+H)⁺; MS (ESI−) m/z375, 411 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 1.41 (d, J 7.1, 3H), 4.17 (s,2H), 4.93 (q, J 7.4, 1H), 7.39 (m, 2H), 7.72 (t, J 7.8, 1H), 7.96 (t, J8.1, 1H), 8.10 (d, J 6.4, 1H), 8.42 (d, J 8.2, 1H), 8.55 (d, J 6.8, 1H),8.71 (d, J 6.8, 1H), 9.07 (d, J 7.5, 1H), 9.86 (s, 1H); Anal. Calcd forC₂₀H₁₆F₄N₂O+1.55 HCl: C, 55.50; H, 4.18; N, 6.52. Found: C, 55.49; H,4.09; N, 6.47.

EXAMPLE 226N-{1-[3-fluoro-4-(trifluoromethyl)phenyl]propyl}-2-(5-isoquinolinyl)acetamide

The title compound was prepared using the procedure described in Example222B using 1-[3-fluoro-4-(trifluoromethyl)phenyl]propylamine instead of4-(trifluoromethoxy)benzylamine. MS (ESI+) m/z 391 (M+H)⁺; MS (ESI⁻) m/z389, 425 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 1.06 (t, J 6.8, 3H), 3.44 (q,J 7.1, 2H), 4.20 (s, 2H), 4.73 (q, J 7.5, 1H), 7.41 (m, 2H), 7.72 (t, J7.8, 1H), 7.97 (t, J 8.2, 1H), 8.12 (d, J 7.1, 1H), 8.44 (d, J 8.1, 1H),8.59 (d, J 6.7, 1H), 8.72 (d, J 6.8, 1H), 9.10 (d, J 8.2, 1H), 9.88 (s,1H); Anal. Calcd for C₁₂H₁₈F₄N₂O+1.3 HCl: C, 57.46; H, 4.70; N, 6.51.Found: C, 57.62; H, 4.44; N, 6.40.

EXAMPLE 2272-(3-methyl-5-isoquinolinyl)-N-[4-(trifluoromethyl)benzyl]acetamideEXAMPLE 227A ethyl (3-methyl-5-isoquinolinyl)acetate

The title compound was prepared using the procedure described in Example221 using 5-bromo-3-methylisquinoline instead of 5-bromoisoquinoline. MS(ESI+) m/z 230 (M+H)⁺; MS (ESI−) m/z 228 (M−H)⁻; ¹H NMR (DMSO, 300 MHz)δ 1.18 (t, J=7.1, 3H), 2.63 (s, 3H), 4.10 (m, 5H), 7.54 (t, J=7.1, 1H),7.65 (m, 2H), 8.01 (d, J 8.1, 1H), 9.22 (s, 1H).

EXAMPLE 227B (3-methyl-5-isoquinolinyl)acetic acid

The title compound was prepared using the procedure described in Example222A using ethyl (3-methyl-5-isoquinolinyl)acetate instead of ethyl5-isoquinolinylacetate. MS (ESI+) m/z 202 (M+H)⁺; MS (ESI−) m/z 200, 156(M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 2.62 (s, 3H), 4.03 (s, 2H), 7.58 (t, J8.2, 1H), 7.64 (m, 2H), 7.99 (d, J 8.1, 1H), 9.21 (s, 1H), 12.46 (s,1H); Anal. Calcd for C₁₂H₁₁NO₂: C, 71.63; H, 5.51; N, 6.96. Found: C,71.00; H, 5.42; N, 6.79.

EXAMPLE 227C2-(3-methyl-5-isoquinolinyl)-N-[4-(trifluoromethyl)benzyl]acetamide

The title compound was prepared using the procedure described in Example222B using (3-methyl-5-isoquinolinyl)acetic acid and4-(trifluoromethyl)benzylamine instead of 5-isoquinolinylacetic acid and4-(trifluoromethoxy)benzylamine. MS (ESI+) m/z 359 (M+H)⁺; MS (ESI−) m/z357 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 2.77 (s, 3H), 4.12 (s, 2H), 4.37(d, J 6.1, 2H), 7.47 (d, J 7.8, 2H), 7.68 (d, J 8.1, 2H), 7.86 (t, J7.4, 1H), 8.03 (d, J 6.4, 1H), 8.36 (m, 2H), 9.03 (t, J 5.8, 1H), 9.77(s, 1H); Anal. Calcd for C₂₀H₁₇F₃N₂O+1.85 HCl: C, 56.44; H, 4.57. Found:C, 56.41; H, 4.46.

EXAMPLE 228N-[3-fluoro-4-(trifluoromethyl)benzyl]-2-(3-methyl-5-isoquinolinyl)acetamide

The title compound was prepared using the procedure described in Example222B using (3-methyl-5-isoquinolinyl)acetic acid and3-fluoro-4-(trifluoromethyl)benzylamine instead of 5-isoquinolinylaceticacid and 4-(trifluoromethoxy)benzylamine. MS (ESI+) m/z 377 (M+H)⁺; MS(ESI−) m/z 375 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 2.77 (s, 3H), 4.14 (s,2H), 4.38 (d, J 6.1, 2H), 7.33 (m, 2H), 7.72 (t, J 7.8, 1H), 7.86 (t, J7.5, 1H), 8.04 (d, J 6.8, 1H), 8.36 (m, 2H), 9.07 (t, J 6.1, 1H), 9.77(s, 1H); Anal. Calcd for C₂₀H₁₆F₄N₂O+1.2 HCl+0.3 DMF: C, 56.62; H, 4.20;N, 7.48 Found: C, 56.79; H, 4.40; N, 7.29.

EXAMPLE 2292-(5-isoquinolinyl)-N-{2-[3-(trifluoromethyl)phenyl]ethyl}acetamide

The title compound was prepared using the procedure described in Example222B using 2-[3-(trifluoromethyl)phenyl]ethylamine instead of4-(trifluoromethoxy)benzylamine. MS (ESI+) m/z 359 (M+H)⁺; MS (ESI−) m/z357, 393 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 2.83 (t, J 7.1, 2H), 3.35 (q,J 6.8, 2H), 4.03 (s, 2H), 7.50 (m, 4H), 7.98 (m, 2H), 8.47 (m, 3H), 8.68(d, J 6.8, 1H), 9.89 (s, 1H); Anal. Calcd for C₂₀H₁₇F₃N₂O+1.55 HCl: C,57.94; H, 4.64; N, 6.73. Found: C, 57.90; H, 4.51; N, 6.75.

EXAMPLE 230 N-(3,3-diphenylpropyl)-2-(5-isoquinolinyl)acetamide

The title compound was prepared using the procedure described in Example222B using 3,3-diphenylpropylamine instead of4-(trifluoromethoxy)benzylamine. MS (ESI+) m/z 381 (M+H)⁺; MS (ESI−) m/z379 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 2.17 (q, J 7.8, 2H), 2.96 (q, J5.8, 2H), 3.99 (s, 2H), 7.16 (m, 2H), 7.25 (m, 9H), 7.84 (t, J 7.5, 1H),7.93 (d, J 6.5, 1H), 8.29 (m, 3H), 8.63 (d, J 6.5, 1H), 9.64 (s, 1H);Anal. Calcd for C₂₆H₂₄N₂O+1HCl+0.45 H₂O: C, 73.47; H, 6.14; N, 6.59.Found: C, 73.84; H, 6.17; N, 6.07.

EXAMPLE 231 N-(3-butoxypropyl)-2-(5-isoquinolinyl)acetamide

The title compound was prepared using the procedure described in Example222B using 3-butoxypropylamine instead of4-(trifluoromethoxy)benzylamine. MS (ESI+) m/z 301 (M+H)⁺; MS (ESI−) m/z299 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 0.85 (t, J 7.5, 3H), 1.28 (m, 2H),1.43 (m, 2H), 1.63 (m, 2H), 3.11 (m, 2H), 3.32 (m, 4H), 3.97 (s, 2H),7.81 (t, J 7.2, 1H), 7.89 (d, J 6.8, 1H), 8.22 (m, 3H), 8.63 (d, J 5.9,1H), 9.59 (s, 1H).

EXAMPLE 232 2-(5-isoquinolinyl)-N-(3-phenylpropyl)acetamide

The title compound was prepared using the procedure described in Example222B using 3-phenylpropylamine instead of4-(trifluoromethoxy)benzylamine. MS (ESI+) m/z 305 (M+H)⁺; MS (ESI−) m/z303 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 1.70 (p, J 7.1, 2H), 2.55 (t, J7.1, 2H), 3.07 (q, J 6.8, 2H), 4.05 (s, 2H), 7.21 (m, 5H), 7.92 (t, J7.5, 1H), 8.04 (d, J 6.4, 1H), 8.38 (m, 2H), 8.48 (d, J 6.5, 1H), 8.69(d, J 6.5, 1H), 9.79 (s, 1H); Anal. Calcd for C₂₀H₂₀N₂O+1.5 HCl: C,66.97; H, 6.18; N, 8.06. Found: C, 66.90; H, 6.04; N, 7.80.

EXAMPLE 233 2-(5-isoquinolinyl)-N-[2-(2-thienyl)ethyl]acetamide

The title compound was prepared using the procedure described in Example222B using 2-(2-thienyl)ethylamine instead of4-(trifluoromethoxy)benzylamine. MS (ESI+) m/z 297 (M+H)⁺; MS (ESI−) m/z295 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 2.93 (t, J 6.8, 2H), 3.32 (q, J6.9, 2H), 3.96 (s, 2H), 6.83 (d, J 2.5, 1H), 6.93 (q, J 3.4, 1H), 7.31(t, J 3.7, 1H), 7.77 (t, J 8.1, 1H), 7.82 (d, J 7.2, 1H), 8.14 (d, J6.2, 1H), 8.18 (d, J 8.1, 1H), 8.35 (t, J 6.1, 1H), 8.59 (d, J 6.2, 1H),9.53 (s, 1H).

EXAMPLE 234 N-[3-(1H-imidazol-1-yl)propyl]-2-(5-isoquinolinyl)acetamide

The title compound was prepared using the procedure described in Example222B using 3-(1H-imidazol-1-yl)propylamine instead of4-(trifluoromethoxy)benzylamine. MS (ESI+) m/z 295 (M+H)⁺; MS (ESI−) m/z293 (M−H); ¹H NMR (DMSO, 300 MHz) δ 1.96 (m, 2H), 3.07 (q, J 6.9, 2H),3.97 (s, 2H), 4.19 (t, J 6.8, 2H), 7.73 (m, 4H), 8.09 (d, J 5.9, 1H),8.14 (d, J 8.1, 1H), 8.32 (t, J 5.3, 1H), 8.58 (d, J 5.9, 1H), 9.07 (s,1H), 9.46 (s, 1H).

EXAMPLE 2352-(5-isoquinolinyl)-N-[3-(2-oxo-1-pyrrolidinyl)propyl]acetamide

The title compound was prepared using the procedure described in Example222B using 1-(3-aminopropyl)-2-pyrrolidinone instead of4-(trifluoromethoxy)benzylamine. MS (ESI+) m/z 312 (M+H)⁺; MS (ESI−) m/z310 (M−H); ¹H NMR (DMSO, 300 MHz) δ 1.59 (p, J 7.5, 15.3, 2H), 1.89 (p,J 7.2, 14.0, 2H), 2.19 (t, J 8.2, 2H), 3.04 (q, J 5.9, 2H), 3.15 (t, J7.1, 2H), 3.28 (t, J 7.2, 2H), 3.99 (s, 2H), 7.81 (t, J 7.2, 1H), 7.99(d, J 6.9, 1H), 8.23 (m, 3H), 8.63 (d, J 6.3, 1H), 9.60 (s, 1H).

EXAMPLE 236 N-(2,2-diphenylethyl)-2-(5-isoquinolinyl)acetamide

The title compound was prepared using the procedure described in Example222B using 2,2-diphenylethylamine instead of4-(trifluoromethoxy)benzylamine. MS (ESI+) m/z 367 (M+H)⁺; MS (ESI−) m/z365 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 3.73 (q, J 6.0, 2H), 3.83 (s, 2H),4.18 (t, J 8.1, 1H), 7.18 (m, 2H), 7.25 (m, 9H), 7.60 (m, 2H), 7.81 (d,J 6.5, 1H), 8.06 (d, J 8.1, 1H), 8.25 (t, J 4.7, 1H), 8.43 (d, J 5.6,1H), 9.37 (s, 1H).

EXAMPLE 237 N-benzyl-2-(5-isoquinolinyl)acetamide

The title compound was prepared using the procedure described in Example222B using 2,2-diphenylethylamine instead of4-trifluoromethoxy)benzylamine. MS (ESI+) m/z 277 (M+H)⁺; MS (ESI−) m/z275 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 4.05 (s, 2H), 4.29 (d, J 5.9, 2H),7.23 (t, J 5.3, 3H), 7.30 (t, J 3.4, 2H), 7.78 (t, J 7.8, 1H), 7.88 (d,J 6.9, 1H), 8.20 (t, J 7.8, 2H), 8.60 (d, J 6.3, 1H), 8.72 (t, J 5.3,1H), 9.54 (s, 1H).

EXAMPLE 2382-(5-isoquinolinyl)-N-{4-[(trifluoromethyl)thio]benzyl}acetamide

The title compound was prepared using the procedure described in Example222B using 4-[(trifluoromethyl)thio]benzylamine instead of4-(trifluoromethoxy)benzylamine. MS (ESI+) m/z 377 (M+H)⁺; MS (ESI−) m/z375 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 4.06 (s, 2H), 4.35 (d, J 5.9, 2H),7.40 (d, J 8.1, 2H), 7.66 (d, J 8.2, 2H), 7.75 (t, J 7.5, 1H), 7.85 (d,J 6.6, 1H), 8.16 (m, 2H), 8.59 (d, J 5.9, 1H), 8.79 (t, J 5.9, 1H), 9.50(s, 1H).

EXAMPLE 239 2-(5-isoquinolinyl)-N-(2-phenylethyl)acetamide

The title compound was prepared using the procedure described in Example222B using 2-phenylethylamine instead of4-(trifluoromethoxy)benzylamine. MS (ESI+) m/z 291 (M+H)⁺; MS (ESI−) m/z289 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 2.71 (t, J 7.1, 2H), 3.31 (q, J7.1, 2H), 3.94 (s, 2H), 7.17 (m, 3H), 7.25 (t, J 7.5, 2H), 7.77 (t, J7.5, 1H), 7.82 (d, J 6.6, 1H), 8.15 (d, J 6.2, 1H), 8.19 (d, J 7.8, 1H),8.27 (t, J 5.3, 1H), 8.59 (d, J 5.0, 1H), 9.55 (s, 1H).

EXAMPLE 240 2-(5-isoquinolinyl)-N-[2-(3-pyridinyl)ethyl]acetamide

The title compound was prepared using the procedure described in Example222B using 2-(2-pyridinyl)ethylamine instead of4-(trifluoromethoxy)benzylamine. MS (ESI+) m/z 292 (M+H)⁺; MS (ESI−) m/z290 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 2.84 (t, J 6.9, 2H), 3.39 (q, J6.5, 21H), 3.92 (s, 2H), 7.58 (t, J 5.3, 1H), 7.75 (m, 2H), 7.97 (d, J7.8, 1H), 8.05 (d, J 5.9, 1H), 8.16 (d, J 7.8, 1H), 8.29 (t, J 5.6, 1H),8.57 (m, 3H), 9.51 (s, 1H).

EXAMPLE 241N-{1-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl}-N′-5-isoquinolinylurea

The title compound was prepared using the procedure described in Example61B using 1-[3-fluoro-4-(trifluoromethyl)phenyl]ethylamine instead of4-cyanobenzyl alcohol. MS (ESI+) m/z 378 (M+H)⁺; MS (ESI−) m/z 376(M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 1.46 (d, J 7.1, 3H), 4.97 (p, J 7.1,1H), 7.51 (m, 2H), 7.77 (t, J 7.8, 1H), 7.86 (t, J 8.2, 1H), 7.99 (d, J7.1, 1H), 8.06 (d, J 8.1, 1H), 8.58 (d, J 6.8, 1H), 8.71 (d, J 6.8, 1H),8.78 (d, J 6.8, 1H), 9.62 (s, 1H), 9.76 (s, 1H); Anal. Calcd forC₁₉H₁₅F₄N₃O+1 HCl: C, 54.93; H, 3.99; N, 10.09. Found: C, 55.15; H,3.90; N, 10.15.

EXAMPLE 242N-{1-[3-fluoro-4-(trifluoromethyl)phenyl]propyl}-N′-5-isoquinolinylurea

The title compound was prepared using the procedure described in Example61B using 1-[3-fluoro-4-(trifluoromethyl)phenyl]propylamine instead of4-cyanobenzyl alcohol. MS (ESI+) m/z 392 (M+H)⁺; MS (ESI−) m/z 390(M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 0.94 (t, J 7.4, 3H), 1.78 (m, 2H), 4.80(q, J 7.5, 1H), 7.59 (m, 2H), 7.77 (t, J 8.1, 1H), 7.84 (t, J 8.2, 1H),7.96 (d, J 8.2, 1H), 8.04 (d, J 8.1, 1H), 8.56 (d, J 7.1, 1H), 8.73 (m,2H), 9.59 (s, 1H), 9.73 (s, 1H); Anal. Calcd for C₂₀H₁₇F₄N₃O+1 HCl: C,56.10; H, 4.26; N, 9.81. Found: C, 56.15; H, 4.24; N, 9.82.

EXAMPLE 243N-[3-bromo-4-(trifluoromethyl)benzyl]-2-(5-isoquinolinyl)acetamideEXAMPLE 243A 3-bromo-4-trifluoromethylbenzoic acid

3-Amino-4-trifluoromethylbenzoic acid (8.20 g, 40.0 mmol), preparedaccording to Astrid Giencke and Helmut Lackner, Liebigs Ann. Chem.,569-579:6 (1990), in 48% HBr (20 mL) and H₂O (67 mL) at 0° C. wastreated with NaNO₂ (2.99 g) in small portions over 15 minutes. Afterstirring for 30 minutes, the mixture was treated with urea (0.250 g) andthen the mixture was added dropwise to a solution of CuBr (10.0 g) in48% HBr (40 mL) and H₂O (100 mL). The reaction mixture was heated at 75°C., stirred for 2 hours, cooled to room temperature, and stirredovernight. The mixture was treated with with 20% NaOH until the pH>10.The resulting blue copper salts were removed by filtration throughCelite. The mixture was acidified to pH 1 with HCl, extracted withCH₂Cl₂(3×200 mL), dried over Na₂SO₄, filtered, and the filtrate wasconcentrated under reduced pressure to provide the title compound.

EXAMPLE 243B 3-bromo-4-(trifluoromethyl)benzamide

The product from Example 243A (4.00 g, 14.9 mmol) in thionyl chloride(20 mL) was heated at 80° C. for 2 hours. The mixture was concentratedunder reduced pressure and the residue was dissolved in MeOH (30 mL) andcooled to −60° C. The mixture was treated with ammonium hydroxide(10 mL)and allowed to reach room temperature over 3 hours. The solvent wasremoved to give crude 3-bromo-4-trifluoromethylbenzamide. mp 148-150° C.

EXAMPLE 243C 3-bromo-4-(trifluoromethyl)benzylamine

LiAlH₄ (0.906 g, 23.9 mmol) was suspended in 60 mL of dry THF and cooledto 0° C. The mixture was treated with the product from Example 243B (3.2g, 11.9 mmol) in THF (10 mL) dropwise with stirring. After 20 minutes,the mixture was warmed to room temperature 12 hours and treated insuccession with ethyl acetate (2 mL), NaOH (50%, 5 mL), and diethylether (100 mL). The organic phase decanted, dried (Na₂SO₄), filtered andthe filtrate was concentrated under reduced pressure to provide thetitle compound.

EXAMPLE 243DN-[3-bromo-4-(trifluoromethyl)benzyl]-2-(5-isoquinolinyl)acetamide

The title compound was prepared using the procedure described in Example222B using 3-bromo-4-(trifluoromethyl)benzylamine instead of4-(trifluoromethoxy)benzylamine. MS (ESI+) m/z 425, 423 (M+H)⁺; MS(ESI−) m/z 423, 421 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 4.09 (s, 2H), 4.36(d, J 6.1, 2H), 7.43 (d, J 7.2, 2H), 7.67 (s, 1H), 7.79 (m, 2H), 7.90(d, J 7.9, 1H), 8.22 (m, 2H), 8.61 (d, J 6.4, 1H), 8.86 (t, J 6.8, 1H),9.56 (s, 1H); Anal. Calcd for C₁₉H₁₄BrF₃N₂O+0.9 TFA: C, 47.51; H,2.86;N, 5.33. Found: C, 47.53; H, 2.92; N, 5.22.

EXAMPLE 244 N-(4-bromo-3-methylbenzyl)-2-(5-isoquinolinyl)acetamideEXAMPLE 244A 4-bromo-3-methylbenzylamine

LiAlH₄ (0.68 g) in diethyl ether (30 mL) was treated with4-bromo-3-methylbenzonitrile (15 mmol) and refluxed for 2 hours. Themixture was cooled to 0° C. and treated in succession with water (0.7mL), 20% NaOH (0.5 mL), and water (2.5 mL). The mixture was filteredthrough a celite pad and the filter cake was washed several times withdiethyl ether. The filtrate was dried over Na₂SO₄, filtered, and thefiltrate was concentrated under reduced pressure to provide the titlecompound. MS (ESI+) m/z 194 (M+H)⁺; MS (ESI−) m/z 192 (M−H)⁻; ¹H NMR(DMSO, 300 MHz) δ 3.97 (s, 2H), 7.30 (m, 1H), 7.46 m, 2H).

EXAMPLE 244B N-(4-bromo-3-methylbenzyl)-2-(5-isoquinolinyl)acetamide

The title compound was prepared using the procedure described in Example222B using 4-bromo-3-methylbenzylamine instead of4-(trifluoromethoxy)benzylamine. MS (ESI+) m/z 371, 369 (M+H)⁺; MS(ESI−) m/z 369, 367 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 2.28 (s, 3H), 4.13(s, 2H), 4.22 (d, J 6.1, 2H), 7.00 (d, J 8.1, 1H), 7.10 (s, 1H), 7.50(d, J 8.1, 1H), 7.92 (m, 1H), 8.05 (d, J 7.1, 1H), 8.38 (d, J 8.1, 1H),8.48 (d, J 6.8, 1H), 8.70 (d, J 6.8, 1H), 8.86 (t, J 6.8, 1H), 9.80 (s,1H); Anal. Calcd for C₁₉H₁₇BrN₂O+1.1 HCl: C, 55.75; H, 4.46; N, 6.84.Found: C, 55.76; H, 4.23; N, 6.93.

EXAMPLE 245N-[2,4-bis(trifluoromethyl)benzyl]-2-(5-isoquinolinyl)acetamide

The title compound was prepared using the procedure described in Example222B using 2,4-bis(trifluoromethyl)benzylamine instead of4-(trifluoromethoxy)benzylamine. MS (ESI+) m/z 413 (M+H)⁺; MS (ESI−) m/z411 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) rotamers δ 4.22 (s, 2H), 4.53 (d, J6.1, 2H), 5.97 (d, J 6.4, 1H), 7.57-8.48 (m, 6H), 8.72 (d, J 6.4, 1H),8.84 (m, 1H), 9.12 (t, J 6.8, 1H), 9.73 (s, 1H), 9.82 (s, 1H); Anal.Calcd for C₂₀H₁₄F₆N₂O 1.2 HCl: C, 52.67; H, 3.36; N, 6.14. Found: C,52.67; H, 3.21; N, 6.09.

EXAMPLE 246N-[2-chloro-4-(trifluoromethyl)benzyl]-2-(5-isoquinolinyl)acetamideEXAMPLE 246A 2-chloro-4-(trifluoromethyl)benzylamine

The title compound was prepared using the procedure described in Example244A using 2-chloro-4-(trifluoromethyl)benzonitrile instead of4-bromo-3-methylbenzonitrile. MS (ESI+) m/z 209 (M+H)⁺; ¹H NMR (DMSO,300 MHz) δ 3.97 (s, 2H), 7.50-7.70 (m, 3H).

EXAMPLE 246BN-[2-chloro-4-(trifluoromethyl)benzyl]-2-(5-isoquinolinyl)acetamide

The title compound was prepared using the procedure described in Example222B using 2-chloro-4-(trifluoromethyl)benzylamine instead of4-(trifluoromethoxy)benzylamine. MS (ESI+) m/z 379 (M+H)⁺; MS (ESI−) m/z377 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 4.19 (s, 2H), 4.41 (d, J 6.1, 2H),7.56 (d, J 8.1, 1H), 7.70 (d, J 8.1, 1H), 7.83 (s, 1H), 7.92 (m, 1H),8.06 (d, J 7.1, 1H), 8.37 (d, J 8.1, 1H),8.45 (d, J 6.8, 1H), 8.70 (d, J6.8, 1H), 8.97 (t, J 6.8, 1H), 9.77 (s, 1H); Anal. Calcd forC₁₉H₁₄ClF₃N₂O+1 HCl: C, 54.96; H, 3.64; N, 6.75. Found: C, 54.75; H,3.47; N, 6.90.

EXAMPLE 247N-[2,3-difluoro-4-(trifluoromethyl)benzyl]-2-(5-isoquinolinyl)acetamideEXAMPLE 247A 2,3-difluoro-4-(trifluoromethyl)benzylamine

The title compound was prepared using the procedure described in Example244A using 2,3-difluoro-4-(trifluoromethyl)benzonitrile instead of4-bromo-3-methylbenzonitrile.

EXAMPLE 247BN-[2,3-difluoro-4-(trifluoromethyl)benzyl]-2-(5-isoquinolinyl)acetamide

The title compound was prepared using the procedure described in Example222B using 2,3-difluoro-4-(trifluoromethyl)benzylamine instead of4-(trifluoromethoxy)benzylamine. MS (ESI+) m/z 381 (M+H)⁺; MS (ESI−) m/z379 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) rotamers δ 4.16 (s, 2H), 4.42 (d, J6.1, 2H), 7.35 (m, 1H), 7.59 (m, 1H), 7.93 (m, 1H), 8.07 (m, 1H), 8.39(d, J 7.1, 1H), 8.46 (m, 1H), 8.70 (d, J 6.8, 1H), 9.05 (t, J 6.8, 1H),9.81 (s, 1H); Anal. Calcd for C₁₉H₁₄ClF₃N₂O+1 HCl: C, 54.96; H, 3.64; N,6.75. Found: C, 54.75; H, 3.47; N, 6.90.

EXAMPLE 248 ethyl 2-(5-isoquinolinyl)propanoate

Lithium diisopropylamide (12.75 mL, 2M, 25.5 mmol) in THF (160 mL) at−78° C. under nitrogen was treated with ethyl 5-isoquinolinylacetate(5.00 g, 23.2 mmol) in THF (5 mL). After stirring for 30 minutes at −78°C., the mixture was treated with HMPA (5.2 mL) and methyl iodide (1.62mL, 25.5 mmol). After stirring for 30 minutes at −78° C., the mixturewas warmed to 0° C. over 1 hour and quenched by addition of saturatedNH₄Cl solution. The mixture was concentrated under reduced pressure to avolume of 10 mL, diluted with ethyl acetate (200 mL), washed with water(100 mL×5), washed with brine, dried with anhydrous MgSO₄, filtered, andthe filtrate was concentrated under reduced pressure to provide thetitle compound. MS (ESI+) m/z 230 (M+H)⁺; MS (ESI−) m/z 228 (M−H)⁻; ¹HNMR (DMSO, 300 MHz) δ 1.53 (d, J 7.1, 3H), 4.35 (d, J 6.1, 2H), 4.47 (q,J 7.1, 1H), 7.18 (m, 2H), 7.70 (m, 3H), 8.05 (m, 2H), 8.53 (d, J 6.1,1H), 8.68 (t, J 6.8, 1H), 9.32 (s, 1H); Anal. Calcd for C₂₀H₁₆F₄N₂O+1.25HCl: C, 56.93; H, 4.12; N, 6.64. Found: C, 56.72; H, 4.45;N, 7.03.

EXAMPLE 249N-[3-fluoro-4-(trifluoromethyl)benzyl]-2-(5-isoquinolinyl)propanamideEXAMPLE 249A 2-(5-isoquinolinyl)propanoic acid

Ethyl 2-(5-isoquinolinyl)propanoate (1.00 g, 4.36 mmol) was heated at85° C. in NaOH (25%, 20 mL) for 1 hour. The mixture was allowed to coolto room temperature, acidified to around pH 1 with HCl, and concentratedto a dry residue. The solid was extracted with CHCl₃:isopropyl alcohol(3:1, 50 mL×4). The extracts were combined, filtered, and the filtrateconcentrated under reduced pressure to provide the title compound. MS(ESI+) m/z 202 (M+H)⁺; MS (ESI−) m/z 200 (M−H)⁻; ¹H NMR (DMSO, 300 MHz)δ 1.42 (d, J 7.1, 3H), 4.01 (q, J 7.1, 1H), 7.58 (t,J 8.1, 1H), 7.63 (d,J 7.5, 1H), 7.86 (d, J 8.1, 1H), 8.19 (d, J 6.8, 1H), 8.43 (d, J 6.8,1H), 9.22 (s, 1H); Anal. Calcd for C₁₂H₁₀NO₂Na+0.9 H₂O: C, 60.20; H,4.97; N, 5.85. Found: C, 60.45; H, 5.26; N, 5.46.

EXAMPLE 249BN-[3-fluoro-4-(trifluoromethyl)benzyl]-2-(5-isoquinolinyl)propanamide

The title compound was prepared using the procedure described in Example222B using 3-fluoro-4-(trifluoromethyl)benzylamine and2-(5-isoquinolinyl)propanoic acid instead of4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS(ESI+) m/z 377 (M+H)⁺; MS (ESI−) m/z 375 (M−H)⁻; ¹H NMR (DMSO, 300 MHz)δ 1.53 (d, J 7.1, 3H), 4.35 (d, J 6.1, 2H), 4.47 (q, J 7.1, 1H), 7.18(m, 2H), 7.70 (m, 3H), 8.05 (m, 2H), 8.53 (d, J 6.1, 1H), 8.68 (t, J6.8, 1H), 9.32 (s, 1H); Anal. Calcd for C₂₀H₁₆F₄N₂O+1.25 HCl: C, 56.93;H, 4.12; N, 6.64. Found: C, 56.72; H, 4.45; N, 7.03.

EXAMPLE 250 2-(5-isoquinolinyl)-N-[4-(trifluoromethyl)benzyl]propanamide

The title compound was prepared using the procedure described in Example222B using 4-(trifluoromethyl)benzylamine and2-(5-isoquinolinyl)propanoic acid instead of4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS(ESI+) m/z 359 (M+H)⁺; MS (ESI−) m/z 357 (M−H)⁻; ¹H NMR (DMSO, 300 MHz)δ 1.59 (d, J 7.1, 3H), 4.35 (d, J 6.1, 2H), 4.69 (q, J 7.1, 1H), 7.40(d, J 8.1, 1H), 7.65 (d, J 8.1, 1H), 7.78 (m, 2H), 8.03 (t, 1H), 8.20(d, J 7.1, 1H), 8.47 (d, J 7.8, 1H), 8.65 (br s, 1H), 8.75 (s, 1H), 9.05(t, J 5.8, 1H), 9.93 (s, 1H); Anal. Calcd for C₂₀H₁₇F₃N₂O+1.6 HCl+1.3H₂O: C, 54.58; H, 4.86. Found: C, 54.70; H, 5.10.

EXAMPLE 251 2-(5-isoquinolinyl)-N-[3-(trifluoromethyl)benzyl]propanamide

The title compound was prepared using the procedure described in Example222B using 3-(trifluoromethyl)benzylamine and2-(5-isoquinolinyl)propanoic acid instead of4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS(ESI+) m/z 359 (M+H)⁺; MS (ESI−) m/z 357 (M−H)⁻; ¹H NMR (DMSO, 300 MHz)δ 1.54 (d, J 7.1, 3H), 4.28 (d, J 6.1, 2H), 4.50 (q, J 7.1, 1H), 7.41(s, 1H), 7.49 (m, 2H), 7.56 (m, 1H), 7.80 (t, J 7.8, 1H), 7.95 (d, J7.2, 1H), 8.21 (d, J 8.1, 1H), 8.32 (d, J 6.2, 1H), 8.60 (d, J 6.8, 1H),8.72 (t, J 5.8, 1H), 9.56 (s, 1H).

EXAMPLE 2522-(5-isoquinolinyl)-N-{4-[(trifluoromethyl)thio]benzyl}propanamide

The title compound was prepared using the procedure described in Example222B using 4-[(trifluoromethyl)thio]benzylamine and2-5-isoquinolinyl)propanoic acid instead of4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS(ESI+) m/z 391 (M+H)⁺; MS (ESI−) m/z 389 (M−H)⁻; ¹H NMR (DMSO, 300 MHz)δ 1.57 (d, J 7.1, 3H), 4.33 (d, J 6.1, 2H), 4.65 (q, J 7.1, 1H), 7.33(d, J 8.1, 1H), 7.65 (m, 2H), 7.76 (m, 1H), 7.98 (m, 2H), 8.19 (d, J7.1, 1H), 8.42 (d, J 7.8, 1H), 8.61 (br s, 1H), 8.62 (d, J 6.8, 1H),8.73 (d, J 6.8, 1H), 8.96 (t, J 5.8, 1H), 9.86 (s, 1H); Anal. Calcd forC₂₀H₁₇F₃N₂OS+2.1 HCl: C, 51.44; H, 4.12. Found: C, 51.35; H, 3.91.

EXAMPLE 253 N-(4-bromobenzyl)-2-(5-isoquinolinyl)propanamide

The title compound was prepared using the procedure described in Example222B using 4-bromobenzylamine and 2-(5-isoquinolinyl)propanoic acidinstead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylaceticacid. MS (ESI+) m/z 371, 369 (M+H)⁺; MS (ESI−) m/z 369, 367 (M−H)⁻; ¹HNMR (DMSO, 300 MHz) δ 1.57 (d, J 7.1, 3H), 4.23 (d, J 6.1, 2H), 4.63 (q,J 7.1, 1H), 7.14 (m, 2H), 7.47 (m, 2H), 7.76 (m, 1H), 7.98 (t, J 7.5,1H), 8.17 (d, J 7.1, 1H), 8.43 (d, J 7.8, 1H), 8.69 (br s, 1H), 8.74 (d,J 6.8, 1H), 8.92 (t, J 5.8, 1H), 9.88 (s, 1H); Anal. Calcd forC₁₉H₁₇BrN₂O+1.4 HCl: C, 54.30; H, 4.41; N, 6.66. Found: C, 54.49; H,4.28; N, 6.75.

EXAMPLE 254 N-(4-tert-butylbenzyl)-2-(5-isoquinolinyl)propanamide

The title compound was prepared using the procedure described in Example222B using 4-(tert-butyl)benzylamine and 2-(5-isoquinolinyl)propanoicacid instead of 4-(trifluoromethoxy)benzylamine and5-isoquinolinylacetic acid. MS (ESI+) m/z 347 (M+H)⁺; MS (ESI−) m/z 345(M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 1.56 (d, J 7.1, 3H), 4.22 (d, J 6.1,2H), 4.57 (q, J 7.1, 1H), 7.10 (d, J 8.5, 2H), 7.29 (d, J 8.5, 2H), 7.98(t, J 7.5, 1H), 8.13 (d, J 7.1, 1H), 8.34 (d, J 7.8, 1H), 8.56 (d, J6.8, 1H), 8.69 (m, 2H), 9.78 (s, 1H); Anal. Calcd for C₂₃H₂₆N₂O+1.1HCl:C, 71.46; H, 7.07; N, 7.25. Found: C, 71.13; H, 7.17; N, 7.02.

EXAMPLE 255N-[3-fluoro-5-(trifluoromethyl)benzyl]-2-(5-isoquinolinyl)propanamide

The title compound was prepared using the procedure described in Example222B using 3-fluoro-5-(trifluoromethyl)benzylamine and2-(5-isoquinolinyl)propanoic acid instead of4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS(ESI+) m/z 377 (M+H)⁺; MS (ESI−) m/z 375 (M−H)⁻; ¹H NMR (DMSO, 300 MHz)δ 1.55 (d, J 7.1, 3H), 4.36 (m, 2H), 4.53 (q, J 7.1, 1H), 7.29 (m, 2H),7.49 (d, J 8.7, 1H), 7.80 (t, J 7.8, 1H), 7.93 (d, J 6.5, 1H), 8.21 (d,J 8.1, 1H), 8.31 (d, J 6.4, 1H), 8.60 (d, J 6.2, 1H), 8.73 (t, J 5.8,1H), 9.56 (s, 1H).

EXAMPLE 2562-(5-isoquinolinyl)-N-[4-(trifluoromethoxy)benzyl]propanamide

The title compound was prepared using the procedure described in Example222B using 2-(5-isoquinolinyl)propanoic acid instead of5-isoquinolinylacetic acid. MS (ESI+) m/z 375 (M+H)⁺; MS (ESI−) m/z 373(M−H)⁻; H NMR (DMSO, 300 MHz) δ 1.54 (d, J 7.1, 3H), 4.28 (d, J 6.1,2H), 4.50 (q, J 7.1, 1H), 7.28 (q, J 8.5, 4H), 7.79 (t, J 7.8, 1H), 1H),7.93 (d, J 7.2, 1H), 8.18 (d, J 8.1, 1H), 8.26 (d, J 6.2, 1H), 8.59 (d,J 6.8, 1H), 8.65 (t, J 5.8, 1H), 9.53 (s, 1H).

EXAMPLE 2572-(5-isoquinolinyl)-N-[3-(trifluoromethoxy)benzyl]propanamide

The title compound was prepared using the procedure described in Example222B using 3-(trifluoromethoxy)benzylamine and2-(5-isoquinolinyl)propanoic acid instead of4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS(ESI+) m/z 375 (M+H)⁺; MS (ESI−) m/z 373 (M−H)⁻; ¹H NMR (DMSO, 300 MHz)δ 1.54 (d, J 7.1, 3H), 4.28 (d, J 6.1, 2H), 4.50 (q, J 7.1, 1H), 7.05(s, 1H), 7.20 (m, 2H), 7.40 (m, 1H), 7.81 (t, J 7.8, 1H), 7.96 (d, J7.2, 1H), 8.21 (d, J 8.1, 1H), 8.32 (d, J 6.2, 1H), 8.61 (d, J 6.8, 1H),8.70 (t, J 5.8, 1H), 9.57 (s, 1H).

EXAMPLE 258 N-(2,4-dimethylbenzyl)-2-(5-isoquinolinyl)propanamide

The title compound was prepared using the procedure described in Example222B using 2,4-dimethylbenzylamine and 2-(5-isoquinolinyl)propanoic acidinstead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylaceticacid. MS (ESI+) m/z 319 (M+H)⁺; MS (ESI−) m/z 317 (M−H)⁻; ¹H NMR (DMSO,300 MHz) δ 1.52 (d, J 7.1, 3H), 2.13 (s, 3H), 2.21 (s, 3H), 4.20 (m,2H), 4.51 (q, J 7.1, 1H), 6.88 (d, J 7.5, 1H), 6.94 (s, 1H), 6.98 (d, J7.5, 1H), 7.82 (t, J 7.8, 1H), 7.99 (d, J 6.5, 1H), 8.21 (d, J 8.1, 1H),8.35 (d, J 6.4, 1H), 8.44 (t, J 5.8, 1H), 8.62 (d, J 6.2, 1H), 9.57 (s,1H).

EXAMPLE 259 N-(2,5-dimethylbenzyl)-2-(5-isoquinolinyl)propanamide

The title compound was prepared using the procedure described in Example222B using 2,5-dimethylbenzylamine and 2-(5-isoquinolinyl)propanoic acidinstead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylaceticacid. MS (ESI+) m/z 319 (M+H)⁺; MS (ESI−) m/z 317 (M−H)⁻; ¹H NMR (DMSO,300 MHz) δ 1.54 (d, J 7.1, 3H), 2.09 (s, 3H), 2.12 (s, 3H), 4.20 (m,2H), 4.53 (q, J 7.1, 1H), 6.79 (s, 1H), 6.91 (d, J 7.8, 1H), 6.98 (d, J7.8, 1H), 7.83 (t, J 7.8, 1H), 8.00 (d, J 6.5, 1H), 8.21 (d, J 8.1, 1H),8.37 (d, J 6.4, 1H), 8.46 (t, J 5.8, 1H), 8.62 (d, J 6.2, 1H), 9.57 (s,1H).

EXAMPLE 260 N-(2,3-dichlorobenzyl)-2-(5-isoquinolinyl)propanamide

The title compound was prepared using the procedure described in Example222B using 2,3-dichlorobenzylamine and 2-(5-isoquinolinyl)propanoic acidinstead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylaceticacid. MS (ESI+) m/z 359 (M+H)⁺; MS (ESI−) m/z 357 (M−H)⁻; ¹H NMR (DMSO,300 MHz) δ 1.54 (d, J 7.1, 3H), 4.20 (m, 2H), 4.53 (q, J 7.1, 1H), 7.17(d, J 7.8, 1H), 7.26 (t, J 7.8, 1H), 7.52 (d, J 8.1, 1H), 7.78 (t, J7.8, 1H), 7.91 (d, J 6.5, 1H), 8.16 (d, J 8.1, 1H), 8.24 (d, J 6.4, 1H),8.59 (d, J 6.2, 1H), 8.66 (t, J 5.8, 1H), 9.50 (s, 1H).

EXAMPLE 261 N-(2,4-dichlorobenzyl)-2-(5-isoquinolinyl)propanamide

The title compound was prepared using the procedure described in Example222B using 2,4-dichlorobenzylamine and 2-(5-isoquinolinyl)propanoic acidinstead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylaceticacid. MS (ESI+) m/z 359 (M+H)⁺; MS (ESI−) m/z 357 (M−H)⁻; ¹H NMR (DMSO,300 MHz) δ 1.54 (d, J 7.1, 3H), 4.20 (m, 2H), 4.53 (q, J 7.1, 1H), 7.22(d, J 8.4, 1H), 7.33 (m, 2H), 7.56 (s, 1H), 7.78 (t, J 7.8, 1H). 7.90(d, J 6.5, 1H), 8.17 (d, J 8.1, 1H), 8.25 (d, J 6.4, 1H), 8.62 (m, 2H),9.51 (s, 1H).

EXAMPLE 262 N-(2,5-dichlorobenzyl)-2-(5-isoquinolinyl)propanamide

The title compound was prepared using the procedure described in Example222B using 2,5-dichlorobenzylamine and 2-(5-isoquinolinyl)propanoic acidinstead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylaceticacid. MS (ESI+) m/z 359 (M+H)⁺; MS (ESI−) m/z 357 (M−H)⁻; ¹H NMR (DMSO,300 MHz) δ 1.54 (d, J 7.1, 3H), 4.20 (m, 2H), 4.53 (q, J 7.1, 1H), 7.06(s, 1H), 7.32 (d, J 8.4, 1H), 7.44 (d, J 8.4, 1H), 7.51 (s, 1H), 7.78(t, J 7.8, 1H), 7.90 (d, J 6.5, 1H), 8.16 (d, J 8.1, 1H), 8.26 (d, J6.4, 1H), 8.60 (d, J 6.2, 1H), 8.65 (t, J 5.8, 1H), 9.49 (s, 1H).

EXAMPLE 263 N-(3,4-dichlorobenzyl)-2-(5-isoquinolinyl)propanamide

The title compound was prepared using the procedure described in Example222B using 3,4-dichlorobenzylamine and 2-(5-isoquinolinyl)propanoic acidinstead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylaceticacid. MS (ESI+) m/z 359 (M+H)⁺; MS (ESI−) m/z 357 (M−H)⁻; ¹H NMR (DMSO,300 MHz) δ 1.54 (d, J 7.1, 3H), 4.20 (m, 2H), 4.53 (q, J 7.1, 1H), 7.16(d, J 8.4, 1H), 7.31 (s, 1H), 7.52 (d, J 8.4, 1H), 7.77 (t, J 7.8, 1H),7.89 (d, J 6.5, 1H), 8.16 (d, J 8.1, 1H), 8.22 (d, J 6.4, 1H), 8.59 (d,J 6.2, 1H), 8.64 (t, J 5.8, 1H), 9.49 (s, 1H).

EXAMPLE 264 N-(3,5-dichlorobenzyl)-2-(5-isoquinolinyl)propanamide

The title compound was prepared using the procedure described in Example222B using 3,5-dichlorobenzylamine and 2-(5-isoquinolinyl)propanoic acidinstead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylaceticacid. MS (ESI+) m/z 359 (M+H)⁺; MS (ESI−) m/z 357 (M−H)⁻; ¹H NMR (DMSO,300 MHz) δ 1.54 (d, J 7.1, 3H), 4.20 (m, 2H), 4.53 (q, J 7.1, 1H), 7.13(s, 2H), 7.42 (s, 1H), 7.78 (t, J 7.8, 1H), 7.89 (d, J 6.5, 1H), 8.17(d, J 8.1, 1H), 8.23 (d, J 6.4, 1H), 8.59 (d, J 6.2, 1H), 8.64 (t, J5.8, 1H), 9.51 (s, 1H).

EXAMPLE 265N-[4-(1-azepanyl)-3-fluorobenzyl]-2-(5-isoquinolinyl)acetamide

The title compound was prepared using the procedure described in Example222B using 4-(1-azepanyl)-3-fluorobenzylamine instead of4-(trifluoromethoxy)benzylamine. MS (ESI+) m/z 392 (M+H)⁺; MS (ESI−) m/z390 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 1.53 (m, 4H), 1.72 (m, 4H), 3.32(m, 4H), 3.96 (s, 2H), 4.18 (d, J 6.1, 2H), 6.86 (m, 3H), 7.69 (m, 2H),7.94 (d, J 7.5, 1H), 8.03 (d, J 7.1, 1H), 8.50 (d, J 7.8, 1H), 8.62 (t,J 5.8, 1H), 9.30 (s, 1H); Anal. Calcd for C₂₄H₂₆FN₃O+0.3 H₂O: C, 72.63;H, 6.76; N, 10.59. Found: C, 72.78; H, 7.05; N, 10.80.

EXAMPLE 266 N-[4-(1-azepanyl)benzyl]-2-(5-isoquinolinyl)propanamide

The title compound was prepared using the procedure described in Example222B using 4-(1-azepanyl)benzylamine and 2-(5-isoquinolinyl)propanoicacid instead of 4-(trifluoromethoxy)benzylamine and5-isoquinolinylacetic acid. MS (ESI+) m/z 388 (M+H)⁺; MS (ESI−) m/z 366(M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 1.53 (m, 7H), 1.72 (m, 4H), 3.85 (s,2H), 4.03 (q, J 7.1, 1H), 6.76 (m, 3H), 7.26 (m, 2H), 7.58 (m, 1H), 1H),8.10 (m, 2H), 8.72 (t, J 5.8, 1H), 9.91 (s, 1H); Anal. Calcd forC₂₅H₂₉N₃O+2.15 HCl+2 H₂O: C, 59.82; H, 7.06. Found: C, 59.59; H, 728.

EXAMPLE 267N-[4-(1-azepanyl)-3-fluorobenzyl]-2-(5-isoquinolinyl)propanamide

The title compound was prepared using the procedure described in Example222B using 4-(1-azepanyl)-3-fluorobenzylamine and2-(5-isoquinolinyl)propanoic acid instead of4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS(ESI+) m/z 406 (M+H)⁺; MS (ESI−) m/z 404 (M−H)⁻; ¹H NMR (DMSO, 300 MHz)δ 1.53 (m, 7H), 1.72 (m, 4H), 3.32 (m, 4H), 3.65 (s, 2H), 4.18 (q, J7.1, 1H), 6.86 (m, 3H), 7.58 (m, 2H), 7.74 (m, 1H), 8.13 (m, 2H), 8.52(d, J 7.8, 1H), 9.30 (s, 1H); Anal. Calcd for C₂₅H₂₈FN₃O+3.25 HCl: C,57.30; H, 6.01. Found: C, 57.26; H, 5.98.

EXAMPLE 268 ethyl 2-(5-isoquinolinyl)butanoate

The title compound was prepared using the procedure described in Example248 using ethyl iodide instead of methyl iodide. MS (ESI+) m/z 244(M+H)⁺; MS (ESI−) m/z 242 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 1.53 (d, J7.1, 3H), 4.35 (d, J 6.1, 2H), 4.47 (q, J 7.1, 1H), 7.18 (m, 2H), 7.70(m, 3H), 8.05 (m, 2H), 8.53 (d, J 6.1, 1H), 8.68 (t, J 6.8, 1H), 9.32(s, 1H); Anal. Calcd for C₁₅H₁₇NO₂+0.4 H₂O: C, 71.92; H, 7.16; N, 5.59.Found: C, 72.23; H, 7.32; N, 5.31.

EXAMPLE 269N-[3-fluoro-4-(trifluoromethyl)benzyl]-2-(5-isoquinolinyl)butanamideEXAMPLE 269A 2-(5-isoquinolinyl)butanoic acid

The title compound was prepared using the procedure described in Example249A using ethyl 2-(5-isoquinolinyl)butanoate instead of ethyl2-(5-isoquinolinyl)propanoate.

EXAMPLE 269BN-[3-fluoro-4-(trifluoromethyl)benzyl]-2-(5-isoquinolinyl)butanamide

The title compound was prepared using the procedure described in Example222B using 3-fluoro-4-(trifluoromethyl)benzylamine and2-(5-isoquinolinyl)butanoic acid instead of4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS(ESI+) m/z 391 (M+H)⁺; MS (ESI−) m/z 389 (M−H)⁻; ¹H NMR (DMSO, 300 MHz)δ 0.91 (t, J 7.5, 3H), 1.81 (m, 1H), 2.17 (m, 1H), 4.35 (m, 2H), 7.17(m, 2H), 7.69 (t, J 7.8, 1H), 7.86 (t, J 7.8, 1H), 8.04 (d, J 7.1, 1H),8.23 (d, J 8.1, 1H), 8.65 (d, J 6.8, 1H), 8.83 (t, J 6.8, 1H), 9.60 (s,1H); Anal. Calcd for C₂₁H₁₈F₄N₂O+1 HCl: C, 54.77; H, 3.80; N, 5.55.Found: C, 54.62; H, 3.57; N, 5.50.

EXAMPLE 270 2-(5-isoquinolinyl)-N-[4-(trifluoromethyl)benzyl]butanamide

The title compound was prepared using the procedure described in Example222B using 4-(trifluoromethyl)benzylamine and2-(5-isoquinolinyl)butanoic acid instead of4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS(ESI+) m/z 391 (M+H)⁺; MS (ESI−) m/z 371 (M−H)⁻; ¹H NMR (DMSO, 300 MHz)δ 0.91 (t, J 7.5, 3H), 1.91 (m, 1H), 2.19 (m, 1H), 4.38 (m, 2H), 7.38(d, J 8.5, 2H), 7.64 (d, J 8.5, 2H), 7.96 (t, J 7.8, 1H), 8.20 (d, J7.1, 1H), 8.39 (d, J 8.1, 1H), 8.72 (s, 1H), 9.02 (t, J 6.8, 1H), 9.81(s, 1H), 10.12 (br s, 1H); Anal. Calcd for C₂₁H₁₉F₃N₂O: C, 67.73; H,5.14; N, 7.52. Found: C, 67.46; H, 4.90; N, 7.90.

EXAMPLE 271 N-(4-bromobenzyl)-2-(5-isoquinolinyl)butanamide

The title compound was prepared using the procedure described in Example222B using 4-bromobenzylamine and 2-(5-isoquinolinyl)butanoic acidinstead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylaceticacid. MS (ESI+) m/z 385, 383 (M+H)⁺; MS (ESI−) m/z 383, 381 (M−H)⁻; ¹HNMR (DMSO, 300 MHz) δ 0.91 (t, J 7.5, 3H), 1.81 (m, 1H), 2.19 (m, 1H),3.39 (m, 1H), 4.22 (m, 2H), 7.13 (d, J 8.5, 2H), 7.44 (m, 3H), 7.57 (t,J 7.8, 1H), 8.00 (m, 1H), 8.21 (d, J 7.1, 1H), 8.41 (d, J 8.1, 1H), 8.72(s, 1H), 8.93 (t, J 6.8, 1H), 9.81 (s, 1H), 10.16 (br s, 1H); Anal.Calcd for C₂₀H₁₉BrN₂O: C, 62.67; H, 5.00. Found: C, 62.52; H, 4.95.

EXAMPLE 2722-(5-isoquinolinyl)-N-{4-[(trifluoromethyl)thio]benzyl}butanamide

The title compound was prepared using the procedure described in Example222B using 4-[(trifluoromethyl)thio]benzylamine and2-(5-isoquinolinyl)butanoic acid instead of4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS(ESI+) m/z 405 (M+H)⁺; MS (ESI−) m/z 403 (M−H)⁻; ¹H NMR (DMSO, 300 MHz)δ 0.91 (t, J 7.5, 3H), 1.81 (m, 1H), 2.21 (m, 1H), 3.39 (m, 1H), 4.34(m, 2H), 7.31 (m, 2H), 7.58 (m, 2H), 7.62 (d, J 7.8, 1H), 8.00 (m, 2H),8.22 (d, J 7.1, 1H), 8.45 (m, 1H), 8.77 (m, 1H), 8.82 (m, 1H), 9.06 (t,J 6.8, 1H), 9.87 (s, 1H), 10.30 (br s, 1H); Anal. Calcd forC₂₁H₁₉F₃N₂OS+0.65 HCl: C, 58.91; H, 4.63; N, 6.54. Found: C, 59.24; H,4.30; N, 6.60.

EXAMPLE 273N-[4-(1-azepanyl)-3-fluorobenzyl]-2-(5-isoquinolinyl)butanamide

The title compound was prepared using the procedure described in Example222B using 4-(1-azepanyl)-3-fluorobenzylamine and2-(5-isoquinolinyl)butanoic acid instead of4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS(ESI+) m/z 420 (M+H)⁺; MS (ESI−) m/z 418 (M−H)⁻; ¹H NMR (DMSO, 300 MHz)δ 0.90 (t, J 7.5, 3H), δ 1.55 (m, 4H), 1.76 (m, 6H), 2.20 (m, 1H), 3.34(m, 5H), 4.18 (m, 2H), 6.81 (m, 1H), 7.62 (m, 1H), 8.00 (m, 2H), 8.27(d, J 7.1, 1H), 8.45 (d, 1H), 8.77 (d, 1H), 8.82 (m, 1H), 9.90 (s, 1H),10.18 (br s, 1H); Anal. Calcd for C₂₆H₃₀FN₃O+0.45 H₂O: C, 73.02; H,7.28. Found: C, 73.05; H, 7.20.

EXAMPLE 274 ethyl 2-(5-isoquinolinyl)-2-methylpropanoate

The title compound was prepared using the procedure described in Example248 using ethyl 2-(5-isoquinolinyl)propanoate instead of ethyl5-isoquinolinylacetate. MS (ESI+) m/z 244 (M+H)⁺; MS (ESI−) m/z 242(M−H)⁻; ¹H NMR (DMSO, 300 MHz) rotamers δ 0.98, 1.08 (t, J 7.1, 3H),1.67 (s, 6H), 4.58 (q, J 7.1, 1H), 7.53 (m, 1H), 7.82 (m, 1H), 7.97 (m,1H), 8.05 (m, 1H), 8.55, 8.50 (d, J 6.1, 1H), 9.33 (s, 1H).

EXAMPLE 2752-(5-isoquinolinyl)-2-methyl-N-{4-[(trifluoromethyl)thio]benzyl}propanamideEXAMPLE 275A 2-(5-isoquinolinyl)-2-methylpropanoic acid

The title compound was prepared using the procedure described in Example249A using ethyl 2-(5-isoquinolinyl)-2-methylpropanoate instead of ethyl2-5-isoquinolinyl)propanoate.

EXAMPLE 275B2-(5-isoquinolinyl)-2-methyl-N-{4-[(trifluoromethyl)thio]benzyl}propanamide

The title compound was prepared using the procedure described in Example222B using 4-[(trifluoromethyl)thio]benzylamine and2-(5-isoquinolinyl)-2-methylpropanoic acid instead of4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS(ESI+) m/z 405 (M+H)⁺; MS (ESI−) m/z 403 (M−H)⁻; ¹H NMR (DMSO, 300 MHz)δ 1.57 (s, 3H), 1.64 (s, 3H), 4.33 (d, J 6.1, 2H), 6.57 (s, 1H), 7.18(m, 1H), 7.33(m, 1H), 7.52 (m, 2H), 7.82 (m, 1H), 8.11 (m, 1H), 8.36 (d,J 7.8, 1H), 8.57 (m, 1H), 9.42 (s, 1H), 10.08 (s, 1H); Anal. Calcd forC₂₁H₁₉F₃N₂OS+2 HCl: C, 52.84; H, 4.43. Found: C, 52.66; H, 4.39.

EXAMPLE 276 ethyl hydroxy(5-isoquinolinyl)acetate

The title compound was prepared using the procedure described in Example248 using (S) camphorsulfonyloxaziridine (2 equivalents) instead ofmethyl iodide.

EXAMPLE 277N-(4-tert-butylbenzyl)-2-hydroxy-2-(5-isoquinolinyl)acetamide EXAMPLE277A hydroxy(5-isoquinolinyl)acetic acid

The title compound was prepared using the procedure described in Example249A using ethyl hydroxy(5-isoquinolinyl)acetate instead of ethyl2-(5-isoquinolinyl)propanoate. MS (ESI+) m/z 204 (M+H)⁺; MS (ESI−) m/z202 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 4.97 (d, J 3.1, 1H), 5.34 (d, J3.3, 1H), 7.55 (m, 1H), 7.68 (d, J 7.5, 1H), 7.90 (d, J 8.1, 1H), 8.21(d, J 6.8, 1H), 8.40 (d, J 6.8, 1H), 9.22 (s, 1H); Anal. Calcd forC₁₁H₉NO₃+1.9 HCl: C, 51.96; H, 5.00. Found: C, 51.89; H, 5.25.

EXAMPLE 277BN-(4-tert-butylbenzyl)-2-hydroxy-2-(5-isoquinolinyl)acetamide

The title compound was prepared using the procedure described in Example222B using 4-(tert-butyl)benzylamine and hydroxy(5-isoquinolinyl)aceticacid instead of 4-(trifluoromethoxy)benzylamine and5-isoquinolinylacetic acid. [α]²² _(D)-47.2 (c 0.7, MeOH); MS (ESI+) m/z349 (M+H)⁺; MS (ESI−) m/z 347 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 1.26 (s,9H), 3.69 (s, 1H), 4.27 (d, J 6.1, 2H), 5.62 (s, 1H), 6.52 (br s, 1H),7.17 (d, J 8.1, 2H), 7.29 (m, 3H), 7.67 (t, J 8.1, 1H), 7.82 (d, J 7.1,1H), 8.10 (m, 2H), 8.44 (d, J 5.8, 1H), 8.71 (t, J 6.1, 1H), 9.30 (s,1H); Anal. Calcd for C₂₂H₂₄N₂O₂+0.25 H₂O: C, 74.87; H, 7.00; N, 7.94.Found: C, 75.22; H, 7.40; N, 7.80.

EXAMPLE 278N-(4-tert-butyl-3-fluorobenzyl)-2-hydroxy-2-(5-isoquinolinyl)acetamide

The title compound was prepared using the procedure described in Example222B using 3-fluoro-4-(trifluoromethyl)benzylamine andhydroxy(5-isoquinolinyl)acetic acid instead of4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS(ESI+) m/z 379 (M+H)⁺; MS (ESI−) m/z 377 (M−H)⁻; H NMR (DMSO, 300 MHz) δ4.37 (d, J 6.1, 2H), 5.65 (d, 1H), 6.63 (d, 1H), 7.27 (m, 2H), 7.29 (m,3H), 7.67 (m, 2H), 7.82 (d, J 7.1, 1H), 8.15 (m, 2H), 8.44 (d, J 5.8,1H), 8.96 (t, J 6.1, 1H), 9.30 (s, 1H); Anal. Calcd for C₂₂H₂₄N₂O₂+0.25H₂O: C, 74.87; H, 7.00; N, 7.94. Found: C, 75.22; H, 7.40; N, 7.80.

EXAMPLE 279 4-tert-butyl 1-ethyl 2-(5-isoquinolinyl)succinate

The title compound was prepared using the procedure described in Example248 using tert-butyl bromoacetate instead of methyl iodide. MS (ESI+)m/z 330 (M+H)⁺; MS (ESI−) m/z 328 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 1.06(t, J 7.1, 3H), 1.30 (s, 9H), 2.76 (dd, J₁16.7, J₂ 6.1, 1H), 3.14 (dd,J₁ 9.5,J₂ 6.1, 1H), 4.12(q, J 7.1, 1H), 4.76 (dd, J₁ 16.7, J₂ 9.5, 1H),7.70 (m, 2H), 8.05 (m, 2H), 8.58 (d, J 6.1, 1H), 9.34 (s, 1H); Anal.Calcd for C₁₉H₂₃NO₄+1 H₂O: C, 65.69; H, 7.25; N, 4.03. Found: C, 65.37;H, 6.91; N, 3.67.

EXAMPLE 280 tert-butyl4-[(4-tert-butylbenzyl)amino]-3-(5-isoquinolinyl)-4-oxobutanoate EXAMPLE280A 4-tert-butoxy-2-(5-isoquinolinyl)-4-oxobutanoic acid

4-Tert-butyl 1-ethyl 2-(5-isoquinolinyl)succinate (1.00 g, 3.04 mmol)and LiOH (0.29 g) were stirred in MeOH:H₂O (3:1, 20 mL) at roomtemperature for 5 hours. The solution was poured into aqueous H₃PO₄(0.1M, 30 mL) and extracted with CHCl₃:IPA (3:1, 30 mL×3). The extractswere combined, dried (MgSO₄), filtered, and the filtrate wasconcentrated under reduced pressure to provide the title compound. MS(ESI+) m/z 302 (M+H)⁺; MS (ESI−) m/z 300 (M−H)⁻; ¹H NMR (DMSO, 300 MHz)δ 1.28 (s, 9H), 2.74 (dd, J₁ 16.7, J₂ 6.1, 1H), 3.10 (dd, J₁ 9.5, J₂6.1, 1H), 4.68 (dd, J₁ 16.7, J₂ 9.5, 1H), 7.70 (m, 2H), 8.05 (m, 2H),8.57 (d, J 6.1, 1H), 9.33 (s, 1H); Anal. Calcd for C₁₇H₁₉NO₄+1.25 H₂O:C, 63.05; H, 6.69. Found: C, 63.27; H, 6.95.

EXAMPLE 280B tert-butyl4-[(4-tert-butylbenzyl)amino]-3-(5-isoquinolinyl)-4-oxobutanoate

The title compound was prepared using the procedure described in Example222B using 4-(tert-butyl)benzylamine and4-tert-butoxy-2-(5-isoquinolinyl)-4-oxobutanoic acid instead of4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS(ESI+) m/z 447 (M+H)⁺; ¹H NMR (DMSO, 300 MHz) δ 1.23 (s, 9H), 1.25 (s,9H), 2.71 (dd, 1H), 3.02 (dd, 1H), 4.22 (m, 2H), 4.71 (m, 1H), 6.57 (s,1H), 7.08 (d, J 8.5, 2H), 7.24 (d, J 8.5, 2H), 7.67 (m, 1H), 7.78 (m,1H), 8.03 (d, J 7.8, 1H), 8.13 (d, J 7.1, 1H), 8.55 (d, J 6.8, 1H), 8.63(m, 1H), 9.31 (s, 1H); Anal. Calcd for C₂₈H₃₄N₂O₃+1 CH₃CN+0.8 H₂O: C,71,77; H, 7.75; N, 8.37. Found: C, 71.64; H, 7.38; N, 8.16.

EXAMPLE 281 2-[(4-tert-butylbenzyl)amino]-1-(5-isoquinolinyl)-2-oxoethylacetate

The product from Example 277B (100 mg, 0.287 mmol) and DMAP (59 mg,0.480 mmol) in CH₂Cl₂ (1 mL) was treated with acetic anhydride (38 μL).After stirring for 30 minutes, the mixture was treated with CH₂Cl₂ (5mL) and the phases separated. The organic layer was washed with water(10 mL×3), dried (Na₂SO₄), filtered, and the filtrate was concentratedto provide the title compound. MS (ESI+) m/z 391 (M+H)⁺; MS (ESI−) m/z389 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 1.25 (s, 9H), 4.27 (dq, J₁ 14.9, J₂6.1, 2H), 6.56 (s, 1H), 7.09 (d, J 8.5, 2H), 7.28 (d, J 8.5, 2H), 7.72(t, J 7.1, 1H), 7.90 (d, J 6.1, 1H), 8.07 (d, J 6.1, 1H), 8.17 (d, J8.1, 1H), 8.53 (d, J 6.1, 1H), 8.86 (t, J 6.1, 1H), 9.35 (s, 1H); Anal.Calcd for C₂₄H₂₆N₂O₃+0.8 H₂O: C, 71.19; H, 6.87; N, 6.92. Found: C,70.87; H, 6.47; N, 6.92.

EXAMPLE 282 2-[(4-tert-butylbenzyl)amino]-1-(5-isoquinolinyl)-2-oxoethylmethanesulfonate

The product from Example 277B (1.00 g, 2.87 mmol) in pyridine (5 mL) wastreated with methanesulfonyl chloride (5.56 μL, 7.17 mmol). Afterstirring for 30 minutes, the mixture was concentrated under reducedpressure and diluted with CH₂Cl₂ (50 mL). The organic layer was washedwith water (50 mL×3), dried (Na₂SO₄), filtered, and the filtrateconcentrated under reduce pressure to provide the title compound. MS(ESI+) m/z 427 (M+H)⁺; MS (ESI−) m/z 425 (M−H)⁻; ¹H NMR (DMSO, 300 MHz)δ 1.27 (s, 9H), 2.37 (s, 3H), 4.27 (dq, J₁ 14.9, J₂ 6.1, 2H), 6.84 (s,1H), 7.17 (d, J 8.5, 2H), 7.38 (d, J 8.5, 2H), 8.07 (m, 2H), 8.37 (d, J8.1, 1H), 8.60 (d, J 6.1, 1H), 8.97 (m, 1H), 9.21 (t, J 6.1, 1H), 9.96(s, 1H).

EXAMPLE 283N-(4-tert-butylbenzyl)-2-(5-isoquinolinyl)-2-methoxyacetamide

The product from Example 277B (100 mg, 0.287 mmol) in THF (2 mL) wastreated with NaH (95%, 8.7 mg, 0.344 mmol). After stirring at roomtemperature for 20 minutes, the mixture was treated with methyl iodide(1.2 eq, 21.4 μL) and stirred for 1 hour. The mixture was concentratedunder reduced pressure and CH₂Cl₂ (10 mL) was added. The organic layerwas washed with water (5 mL×3), dried (Na₂SO₄), filtered, and thefiltrate concentrated under reduced pressure to provide the titlecompound. MS (ESI+) m/z 363 (M+H)⁺; MS (ESI−) m/z 361 (M−H)⁻; ¹H NMR(DMSO, 300 MHz) rotamers 67 1.25 (s, 9H), 3.32 (s, 3H), 4.27 (d, J 6.1,2H), 5.37 (s, 1H), 7.18 (d, J 8.5, 2H), 7.32 (d, J 8.5, 2H), 7.70 (t, J7.1, 1H), 7.83 (d, J 6.1, 1H), 8.07 (m, 2H), 8.43 (d, J 6.1, 1H), 8.80(t, J 6.1, 1H), 9.35 (s, 1H); Anal. Calcd for C₂₃H₂₆N₂O₂+0.3 H₂O: C,75.09; H, 7.29; N, 7.61. Found: C, 75.02; H, 7.34; N, 7.43.

EXAMPLE 284 N-(4-tert-butylbenzyl)-2-chloro-2-(5-isoquinolinyl)acetamide

The product from Example 182 (300 mg, 0.704 mmol) in toluene (10 mL) wastreated with Bu₄NCl (458 mg, 1.408 mmol) and heated at 100° C. for 12hours. The mixture was concentrated under reduced pressure and dilutedwith CH₂Cl₂ (50 mL). The organic layer was washed with water (50 mL×3),dried (Na₂SO₄), filtered, and the filtrate concentrated under reducedpressure. MS (ESI+) m/z 367 (M+H)⁺; MS (ESI−) m/z 365 (M−H)⁻; ¹H NMR(DMSO, 300 MHz) δ 1.26 (s, 9H), 4.11 (d, J 5.1, 2H), 6.59 (s, 1H), 7.16(d, J 8.1, 2H), 7.36 (d, J 8.1, 2H), 7.97 (d, J 8.1, 2H), 8.30 (d, J7.5, 1H), 8.48 (d, J 8.1, 1H), 8.56 (d, J 6.8, 1H), 8.73 (d, J 6.8, 1H),8.97 (m, 1H), 9.18 (t, J 6.1, 1H), 9.81 (s, 1H); Anal. Calcd forC₂₂H₂₃ClN₂O+1 HCl+1.5 CH₃OH: C, 62.53; H, 6.70; N, 6.21. Found: C,62.75; H, 6.87; N, 6.11.

EXAMPLE 285 N-5-isoquinolinyl-3-[4-(trifluoromethyl)phenyl]acrylamide

5-Aminoisoquinoline (0.50 g, 3.47 mmol) and3-[4-(trifluoromethyl)phenyl]acrylic acid (3.47 mmol) were combined in asealed tube and heated at 175° C. for 16 hours with stirring. Themixture was cooled to room temperature, diluted with MeOH, transferredto a flask, and concentrated under reduced pressure. The residue wastriturated with ethyl acetate and filtered to provide the titlecompound. MS (ESI+) m/z 343 (M+H)⁺; MS (ESI−) m/z 341 (M−H)⁻; ¹H NMR(DMSO, 300 MHz) rotamers δ 6.68 (d, J 15.9, 1H), 7.29 (d, J 15.9, 1H),7.60 (d, J 15.9, 1H), 7.80 (m, 1H), 8.25 (d, J 6.8, 1H), 8.57 (d, J 5.8,1H), 9.35 (s, 1H), 10.36 (s, 1H); Anal. Calcd for C₁₉H₁₃F₃N₂O+2 HCl+0.3H₂O: C, 54.25; H, 3.74; N, 6.66. Found: C, 53.90; H, 3.94; N, 7.20.

EXAMPLE 286 N-5-isoquinolinyl-3-[3-(trifluoromethyl)phenyl]acrylamide

The title compound was prepared using the procedure described in Example285 using 3-[3-(trifluoromethyl)phenyl]acrylic acid instead of3-[4-(trifluoromethyl)phenyl]acrylic acid. MS (ESI+) m/z 343 (M+H)⁺; MS(ESI−) m/z 341 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) rotamers δ 6.72 (d, J15.9, 1H), 6.87 (d, J 7.4, 1H), 7.23 (d, J 8.1, 1H), 7.36 (t, J 7.8,1H), 7.70 (m, 2H), 7.93 (d, J 6.1, 1H), 8.10 (m, 2H), 8.35 (d, J 5.8,1H), 9.09 (s, 1H); Anal. Calcd for C₁₉H₁₃F₃N₂O+2.15 HCl: C, 54.24; H,3.63; N, 6.66. Found: C, 53.96; H, 3.93; N, 6.93.

EXAMPLE 287 3-(4-isopropylphenyl)-N-5-isoquinolinylacrylamide

The title compound was prepared using the procedure described in Example285 using 3-(4-isopropylphenyl)acrylic acid instead of3-[4-(trifluoromethyl)phenyl]acrylic acid. MS (ESI+) m/z 317 (M+H)⁺; MS(ESI−) m/z 315 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 1.24 (d, J 6.8, 3H),2.94 (sept, J 6.8, 1H), 7.10 (d, J 15.6, 1H), 7.35 (d, J 7.4, 2H), 7.61(d, J 8.1, 2H), 7.63 (d, J 15.6, 1H), 7.84 (t, J 7.8, 1H), 8.12 (d, J7.8, 1H), 8.26 (d, J 6.4, 1H), 8.35 (d, J 7.1, 1H), 8.64 (d, J 6.8, 1H),9.56 (s, 1H), 10.35 (s, 1H); Anal. Calcd for C₂₁H₂₀N₂O+0.35 TFA: C,73.15; H, 5.76; N, 7.86. Found: C, 73.02; H, 5.50; N, 7.88.

EXAMPLE 288 N-5-isoquinolinyl-2-phenylcyclopropanecarboxamide

The title compound was prepared using the procedure described in Example285 using 2-phenylcyclopropanecarboxylic acid instead of3-[4-(trifluoromethyl)phenyl]acrylic acid. MS (ESI+) m/z 289 (M+H)⁺; MS(ESI−) m/z 287 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 1.46 (m, 1H), 1.56 (m,1H), 2.46 (m, 2H), 7.24 (m, 3H), 7.32 (m, 2H), 7.82 (t, J 7.8, 1H), 8.10(d, J 7.8, 1H), 8.28 (d, J 6.4, 1H), 8.62 (d, J 6.8, 1H), 9.58 (s, 1H),10.46 (s, 1H); Anal. Calcd for C₁₉H₁₆N₂O+0.65 TFA: C, 67.27; H, 4.63; N,7.73. Found: C, 67.27; H, 4.31; N, 7.52.

EXAMPLE 289 3-(3,4-dichlorophenyl)-N-5-isoquinolinylacrylamide

The title compound was prepared using the procedure described in Example285 using 3-(3,4-dichlorophenyl)acrylic acid instead of3-[4-(trifluoromethyl)phenyl]acrylic acid. MS (ESI+) m/z 344 (M+H)⁺; MS(ESI−) m/z 342 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 7.20 (d, J 15.6, 1H),7.67 (m, 3H), 7.84 (d, J 15.6, 1H), 7.97 (d, J 1.7, 1H), 8.10 (d, J 7.8,1H), 8.22 (d, J 6.4, 1H), 8.35 (d, J 7.1, 1H), 8.64 (d, J 6.8, 1H), 9.53(s, 1H), 10.37 (s, 1H); Anal. Calcd for C₁₈H₁₂Cl₂N₂O+0.75 TFA: C, 54.63;H, 3.00; N,6.53. Found: C, 54.43; H, 2.92; N, 6.39.

EXAMPLE 290 3-(1,1′-biphenyl-4-yl)-N-5-isoquinolinylacrylamide

The title compound was prepared using the procedure described in Example285 using 3-(1,1′-biphenyl-4-yl)acrylic acid instead of3-[4-(trifluoromethyl)phenyl]acrylic acid. MS (ESI+) m/z 351 (M+H)⁺; MS(ESI−) m/z 349 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 7.21 (d, J 15.6, 1H),7.39-7.79 (m, 10H), 7.97 (d, J 7.8, 1H), 8.08 (d, J 6.4, 1H), 8.29 (d, J7.1, 1H), 8.58 (d, J 6.8, 1H), 9.34 (s, 1H); Anal. Calcd forC₂₄H₁₈N₂O+0.85 HCl: C, 75.58; H, 4.98. Found: C, 75.69; H, 4.69.

EXAMPLE 291 3-(3-bromo-4-fluorophenyl)-N-5-isoquinolinylacrylamide

The title compound was prepared using the procedure described in Example285 using 3-(3-bromo-4-fluorophenyl)acrylic acid instead of3-[4-(trifluoromethyl)phenyl]acrylic acid. MS (ESI+) m/z 374, 372(M+H)⁺; MS (ESI−) m/z 372, 370 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 7.14 (d,J 15.6, 1H), 7.50 (t, J 8.8, 1H), 7.65 (d, J 15.6, 1H), 7.76 (m, 1H),7.83 (t, J 7.8, 1H), 8.05 (dd, J₁ 6.8, J₂ 2.1, 1H), 8.11 (d, J 7.8, 1H),8.24 (d, J 6.4, 1H), 8.36 (d, J 7.1, 1H), 8.64 (d, J 6.8, 1H), 9.55 (s,1H), 10.35 (s, 1H); Anal. Calcd for C₁₈H₁₂BrFN₂O+1 TFA: C, 49.5 1; H,2.70; N, 5.77. Found: C, 49.78; H, 2.71; N, 5.768.

EXAMPLE 292 3-(4-tert-butylphenyl)-N-5-isoquinolinylacrylamide

The title compound was prepared using the procedure described in Example285 using 3-(4-tert-butylphenyl)acrylic acid instead of3-[4-(trifluoromethyl)phenyl]acrylic acid. MS (ESI+) m/z 331 (M+H)⁺; MS(ESI−) m/z 329 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 1.31 (s, 9H), 7.10 (d, J15.6, 1H), 7.51 (d, J 8.5, 2H), 7.62 (d, J 8.5, 2H), 7.67 (d, J 15.6,1H), 7.86 (t, J 8.2, 1H), 8.14 (d, J 6.1, 1H), 8.31 (d, J 8.2, 1H), 8.40(d, J 6.1, 1H), 8.66 (d, J 6.1, 1H), 9.60 (s, 1H), 10.39 (s, 1H); Anal.Calcd for C₂₂H₂₂N₂O+1 TFA: C, 64.86; H, 5.22; N, 6.30. Found: C, 64.54;H, 5.13; N, 6.18.

EXAMPLE 2933-[3-fluoro-4-(trifluoromethyl)phenyl]-N-5-isoquinolinylacrylamide

The title compound was prepared using the procedure described in Example285 using 3-[3-fluoro-4-(trifluoromethyl)phenyl]acrylic acid instead of3-[4-(trifluoromethyl)phenyl]acrylic acid. MS (ESI+) m/z 361 (M+H)⁺; MS(ESI−) m/z 359 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 7.30 (d, J 15.6, 1H),7.72-7.85 (m, 4H), 7.91 (t, J 8.2, 1H), 8.13 (d, J 6.1, 1H), 8.24 (d, J8.2, 1H), 8.35 (d, J 6.1, 1H), 8.65 (d, J 6.1, 1H), 9.56 (s, 1H), 10.50(s, 1H); Anal. Calcd for C₁₉H₁₂F₄N₂O+0.8 TFA: C, 54.80; H, 2.86; N,6.20. Found: C, 54.59; H, 2.82; N, 6.06.

EXAMPLE 294 N-(8-bromo-5-isoquinolinyl)-N′-(2,4-dichlorobenzyl)ureaEXAMPLE 294A 8-bromo-5-isoquinolinamine 6,8-dibromo-5-isoquinolinamine

5-Aminoisoquinoline (5.50 g, 38.1 mmol) and aluminium trichloride (15.1g, 113 mmol) were combined and heated at 80° C. in a 3-necked flaskequipped with a dropping funnel, stirrer bar, needle and sintered glasstube. The mixture was treated with bromine (3.04 g, 19.05 mmol) via thesintered glass funnel dropwise. After stirring at 80° C. for 2 hours,the suspension was treated with crushed ice in small portions and thesolution was basified with concentrated sodium hydroxide solution. Theaqueous layer was extracted with ethyl acetate (4×100 mL). The organiclayers were combined, dried (Na₂SO₄), filtered, and the filtrate wasconcentrated under reduced pressure. The residue was purified by columnchromatography (hexanes:ethyl acetate, 3:1) to provide the separatetitle compounds. Monobromo: MS (ESI+) m/z 225 (M+H)⁺; MS (ESI−) m/z 223(M−H)⁻; ¹H NMR (CDCl₃, 300 MHz) δ 4.22 (br s, 2H), 6.83 (d, J 8.1, 1H),7.25 (s, 1H), 7.54 (d, J 5.8, 1H), 7.61 (d, J 8.1, 1H), 8.59 (d, J 5.8,1H), 9.56 (s, 1H); Dibromo: MS (ESI+) m/z 303 (M+H)⁺; MS (ESI−) m/z 301(M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 6.41 (br s, 2H), 7.92 (s, 1H), 8.18 (d,J 6.1, 1H), 8.59 (d, J 6.1, 1H), 9.30 (s, 1H).

EXAMPLE 294B N-(8-bromo-5-isoquinolinyl)-N′-(2,4-dichlorobenzyl)urea

8-Bromo-5-isoquinolinamine (120 mg, 0.52 mmol) in THF:toluene (5 mL,1:4) was treated with 2,4-dichloro-1-(isocyanatomethyl)benzene (108 mg,0.52 mmol) in THF (0.5 mL). After stirring for 16 hours at roomtemperature, the mixture was filtered and the filter cake was driedunder reduced pressure to provide the title compound. MS (ESI+) m/z 426(M+H)⁺; MS (ESI−) m/z 424 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 4.42 (d, 5.8,2H), 7.22 (t, J 5.8, 1H), 7.65 (m, 1H), 7.91 (d, J 8.5, 1H), 8.02 (d, J6.1, 1H), 8.22 (d, J 8.5, 1H), 8.69 (d, J 5.8, 1H), 9.01 (s, 1H), 9.44(s, 1H); Anal. Calcd for C₁₇H₁₂BrCl₂N₃O.HCl+0.25EtOH: C, 44.41; H, 3.14;N, 8.88. Found: C, 44.80; H, 2.76; N, 8.84.

EXAMPLE 295 N-(8-bromo-5-isoquinolinyl)-N′-(4-fluorobenzyl)urea

The title compound was prepard using the procedure described in Example294B using 1-fluoro-4-(isocyanatomethyl)benzene instead of2,4-dichloro-1-(isocyanatomethyl)benzene. MS (ESI+) m/z 376 (M+H)⁺; MS(ESI−) m/z 374 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 4.35 (d, 5.8, 2H), 7.12(m, 1H), 7.18 (m, 2H), 7.40 (m, 1H), 7.91 (d, J 8.5, 1H), 7.99 (d, J6.1, 1H), 8.24 (d, J 8.5, 1H), 8.69 (d, J 5.8, 1H), 8.88 (s, 1H), 9.44(s, 1H); Anal. Calcd for C₁₇H₁₃BrFN₃O: C, 54.56; H, 3.50; N, 11.23.Found: C, 54.61; H, 3.35; N, 11.14.

EXAMPLE 296 N-(8-bromo-5-isoquinolinyl)-N′-(3-fluorobenzyl)urea

The title compound was prepard using the procedure described in Example294B using 1-fluoro-4-(isocyanatomethyl)benzene instead of2,4-dichloro-1-(isocyanatomethyl)benzene. MS (ESI+) m/z 376 (M+H)⁺; MS(ESI−) m/z 374 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 4.39 (d, 5.8, 2H), 7.09(m, 1H), 7.17 (m, 2H), 7.40 (m, 1H), 7.91 (d, J 8.5, 1H), 8.01 (d, J6.1, 1H), 8.23 (d, J 8.5, 1H), 8.69 (d, J 5.8, 1H), 8.93 (s, 1H), 9.44(s, 1H); Anal. Calcd for C₁₇H₁₃BrFN₃O: C, 54.56; H, 3.50; N, 11.23.Found: C, 54.64; H, 3.33; N, 11.19.

EXAMPLE 297 N-[1-(4-chlorophenyl)-1-methylethyl]-N′-5-isoquinolinylureaEXAMPLE 297A 2-(4-chlorophenyl)-2-methylpropanoyl chloride

2-(4-Chlorophenyl)-2-methylpropanoic acid (3.85 g, 19.4 mmol) in toluene(5 mL) and thionyl chloride (5.00 g, 3.1 mL) was heated at 80° C. for 2hours. The mixture was cooled and concentrated under reduced pressure toprovide the title compound.

EXAMPLE 297B 1-chloro-4-(1-isocyanato-1-methylethyl)benzene

The product from Example 297A (4.00 g, 19.4 mmol) in acetone (9 mL) at0° C. ws treated with sodium azide (1.27 g) in water (9 mL) dropwiseover 15 minutes. after stirring for 30 minutes at 0° C., the mixture wasextracted with toluene (20 mL). The toluene solution was dried overMgSO₄, filtered, and the filtrate was heated to reflux for 1 hour. Thecooled solution was concentrated under reduced pressure to provide thetitle compound.

EXAMPLE 297C N-[1-(4-chlorophenyl)-1-methylethyl]-N′-5-isoquinolinylurea

The title compound was prepared using the procedure described in Example60F using 1-chloro-4-(1-isocyanato-1-methylethyl)benzene and5-isoquinolinamine instead of the product from Example 60E and1-bromo-4-(isocyanatomethyl)benzene. MS (ESI+) m/z 355 (M+H)⁺; MS (ESI⁻)m/z 353 (M−H)^(−;) ¹H NMR (DMSO, 300 MHz) δ 1.63 (s, 6H), 7.23 (s, 1H),7.37 (d, J 8.8, 2H), 7.47 (d, J 8.8, 2H), 7.73 (t, J 9.2, 1H), 7.93 (d,J 8.1, 1H), 8.25 (d, J 6.4, 1H), 8.39 (d, J 8.1, 1H), 8.67 (d, J 6.4,1H), 8.87 (s, 1H), 9.58 (s, 1H); Anal. Calcd forC₁₉H₁₈ClN₃O.HCl+0.25EtOH: C, 60.40; H, 5.33; N, 10.54. Found: C, 60.82;H, 5.23; N, 10.45.

EXAMPLE 298 N-(4-bromo-3-methylbenzyl)-N′-5-isoquinolinylurea

The title compound was prepared using the procedure described in Example61B using 4-bromo-3-methylbenzylamine instead of 4-cyanobenzyl alcohol.MS (ESI+) m/z 372, 370 (M+H)⁺; MS (ESI−) m/z 370, 368 (M−H)⁻; ¹H NMR(DMSO, 300 MHz) 62.34 (s, 3H), 4.31 (s, 2H), 4.09 (s, 2H), 7.13 (d, J7.2, 2H), 7.34 (s, 1H), 7.55 (m, 2H), 7.82 (d, J 7.9, 1H), 7.90 (m, 1H),8.09 (d, 1H), 8.65 (m, 2H), 8.80 (d, J 6.4, 1H), 9.68 (s, 1H), 9.79 (s,1H); Anal Calcd for C₁₈H₁₆BrN₃O+1.05 HCl: C, 52.66; H, 4.86; N, 10.24.Found: C, 53.00; H, 4.27; N, 10.37.

EXAMPLE 299N-[2-fluoro-4-(trifluoromethyl)benzyl]-N′-5-isoquinolinylurea EXAMPLE299A 2-fluoro-4-(trifluoromethyl)benzylamine

The title compound was prepared using the procedure described in Example172B using 2-fluoro-4-(trifluoromethyl)benzonitrile instead of4-(4-morpholinyl)benzonitrile. MS (ESI+) m/z 194 (M+H)⁺; MS (ESI−) m/z192 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 3.97 (s, 2H), 7.30 (m, 1H), 7.46 m,2H).

EXAMPLE 299BN-[2-fluoro-4-(trifluoromethyl)benzyl]-N′-5-isoquinolinylurea

The title compound was prepared using the procedure described in Example61B using 2-fluoro-4-(trifluoromethyl)benzylamine instead of4-cyanobenzyl alcohol. MS (ESI+) m/z 364 (M+H)⁺; MS (ESI−) m/z 362(M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 4.51 (d, J 5.8, 2H), 7.65 (m, 4H), 7.90(t, J 8.1, 1H), 8.09 (d, J 7.8, 1H), 8.59 (d, J 7.8, 1H), 8.71 (s, 2H),9.66 (s, 1H), 9.76 (s, 1H); Anal. Calcd for C₁₈H₁₃F₄N₃O+1 HCl: C, 54.08;H, 3.53; N, 10.51. Found: C, 54.40; H, 3.60; N, 10.61.

EXAMPLE 300 N-(4-bromobenzyl)-N′-(3-hydroxy-5-isoquinolinyl)urea EXAMPLE300A 5-nitro-3-isoquinolinyl

3-Hydroxyisoquinoline (1.09 g, 7.53 mmol) in concentrated H₂SO₄ (20 mL)at 0° C. was treated with NaNO₃ (0.71 g, 8.34 mmol) in concentratedH₂SO₄ (5 mL) dropwise over 15 minutes. After stirring for 90 minutes,the mixture was allowed to warm to room temperature, stir for 2 hours,poured over an ice-NH₄Cl mixture, and the pH was adjusted to 7-8 with50% NaOH solution. The mixture was filtered and the filter cake dried toprovide the title compound. Structure analysis determined a 2:1 mixtureof the 5-nitro and 7-nitro isomers which were not separated. MS (ESI+)m/z 191 (M+H)⁺; MS (ESI−) m/z 189 (M−H)⁻; ¹H NMR (DMSO, 300 MHz)δ 4.60(s, 1H), 7.48 (t, J 8.0, 1H), 7.57 (s, 1H), 8.42 (d, J 8.0, 1H), 8.57(d, J 7.7, 1H), 9.19 (s, 1H).

EXAMPLE 300B 5-nitro-3-isoquinolinyl acetate

5-Nitro-3-isoquinolinol (3.40 g, 17.9 mmol) in acetic anhydride (40 mL)was treated with acetic acid (5 mL) and pyridine (5 mL) and heated at120° C. for 2 hours. The mixture was cooled to room temperature andconcentrated under reduced pressure to provide the title compound whichwas used in the next step without further purification. MS (ESI+) m/z233 (M+H)⁺; MS (ESI−) m/z 231 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) isomers52.39 (s, 3H), 7.88 (m, 1H), 8.27 (m, 1H), 8.50 (m, 1H), 8.65, 8.74 (d,J 7.8, 1H), 9.47, 9.55 (s, 1H).

EXAMPLE 300C 5-amino-3-isoquinolinyl acetate

5-Nitro-3-isoquinolinyl acetate (50 mg, 0.21 mmol) in 1,4-dioxane (20mL) was treated with Raney-nickel powder (85 mg) and exposed to ahydrogen atmosphere via a balloon for 16 hours. The mixture was filteredthrough a plug of Celite and the filtrate was concentrated under reducedpressure to provide the title compound which was used without furtherpurification.

EXAMPLE 300D N-(4-bromobenzyl)-N′-(3-hydroxy-5-isoquinolinyl)urea

5-Amino-3-isoquinolinyl acetate in toluene:THF (5:1, 5 mL) was treatedwith 1-bromo-4-(isocyanatomethyl)benzene (105 mg). After stirring for 1hour, the mixture was concentrated under reduced pressure and theresidue dissolved in MeOH (20 mL) and treated with K₂CO₃ (4 eq) andstirred for 16 hours. The mixture was concentrated under reducedpressure and partitioned between CH₂Cl₂ and water. The aqueous phase wasseparated and the pH was adjusted to approximately 6 with HCl. Theacidified solution was filtered, and the filter cake was dried. Thesolid was purified by reverse-phase chromatography (using TFA as eluent)to provide the title compound. MS (ESI+) m/z 374, 372 (M+H)⁺; MS (ESI−)m/z 372, 370 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 4.33 (d, J 5.8, 2H), 7.06(m, 1H), 7.29 (m, 3H), 7.57 (m, 3H), 8.07 (d, J 7.8, 1H), 8.48 (s, 1H),8.80 (s, 1H), 8.87 (s, 1H); Anal. Calcd for C₁₇H₁₄BrN₃O₂+0.2 TFA: C,53.08; H, 3.42; N, 10.43. Found: C, 52.91; H, 3.62; N, 10.43.

EXAMPLE 301N-5-isoquinolinyl-N′-{[5-(trifluoromethyl)-2-pyridinyl]methyl}ureaEXAMPLE 301A 5-(trifluoromethyl)-2-pyridinecarbonitrile

Copper (I) cyanide (14.1 g) and 2-bromo-5-trifluoromethylpyridine (3.00g, 13.3 mmol) in dry DMSO (70 mL) were combined and heated at 180° C.for 2 hours, cooled, and poured into NH₄OH (3M). The mixture was thenextracted with ethyl acetate (3×500 mL), washed with water (1×200 mL),dried (MgSO₄), filtered and the filtrate concentrated under reducedpressure to provide the title compound. ¹H NMR (DMSO, 300 MHz) δ 8.22(m, 1H), 8.42 (m, 1H), 9.01 (s, 1H).

EXAMPLE 301B [5-(trifluoromethyl)-2-pyridinyl]methylamine

The title compound was prepared using the procedure described in Example172B using 5-(trifluoromethyl)-2-pyridinecarbonitrile instead of4-(4-morpholinyl)benzonitrile.

EXAMPLE 301CN-5-isoquinolinyl-N′-{[5-(trifluoromethyl)-2-pyridinyl]methyl}urea

The title compound was prepared using the procedure described in Example61B using [5-(trifluoromethyl)-2-pyridinyl]methylamine instead of4-cyanobenzyl alcohol. ¹H NMR (DMSO, 300 MHz) δ 4.51 (m, 2H), 7.97 (m,2H), 8.12 (m, 1H), 8.47 (d, J 7.8, 1H), 8.72 (m, 3H), 9.13 (d, J 6.8,1H), 9.78 (m, 2H), 10.80 (s, 1H); Anal. Calcd for C₁₇H₁₃F₃N₄O+0.8HCl+0.7 CH₃OH: C, 53.43; H, 4.20; N, 14.08. Found: C, 53.41; H, 4.31; N,14.11.

EXAMPLE 302 N-[3-bromo-4-(trifluoromethyl)benzyl]-N′-5-isoquinolinylurea

The title compound was prepared using the procedure described in Example61B using 3-bromo-4-(trifluoromethyl)benzylamine instead of4-cyanobenzyl alcohol. MS (ESI+) m/z 426, 424 (M+H)⁺; MS (ESI−) m/z 424,422 (M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 4.46 (d, J 5.8, 2H), 7.26 (t, J6.1, 1H), 7.56 (d, J 8.8, 1H), 7.90 (m, 2H), 7.97 (d, J 8.1, 1H), 8.21(d, J 6.4, 1H), 8.39 (d, J 8.8, 1H), 8.64 (d, J 6.4, 1H), 9.08 (s, 1H),9.57 (s, 1H); Anal. Calcd for C₁₈H₁₃BrF₃N₃O+0.9 TFA: C, 45.14; H, 2.66;N, 798. Found: C, 45.18; H, 2.64; N, 7.86.

EXAMPLE 303 N-[2,4-bis(trifluoromethyl)benzyl]-N′-5-isoquinolinylurea

The title compound was prepared using the procedure described in Example61B using 2,4-bis(trifluoromethyl)benzylamine instead of 4-cyanobenzylalcohol. MS (ESI+) m/z 414 (M+H)⁺; MS (ESI−) m/z 412 (M−H)⁻; ¹H NMR(DMSO, 300 MHz) rotamers δ 4.63 (d, J 5.8, 2H), 7.70-8.20 (m, 6H), 8.60(m, 3H), 9.60 (m, 2H); Anal. Calcd for C₁₉H₁₃F₆N₃O+1 HCl: C, 50.74; H,3.14; N, 9.34. Found: C, 50.88; H, 3.08; N, 9.10.

EXAMPLE 304N-[2,3-difluoro-4-(trifluoromethyl)benzyl]-N′-5-isoquinolinylurea

The title compound was prepared using the procedure described in Example61B using 2,3-difluoro-4-(trifluoromethyl)benzylamine instead of4-cyanobenzyl alcohol. MS (ESI+) m/z 382 (M+H)⁺; MS (ESI−) m/z 380(M−H)⁻; ¹H NMR (DMSO, 300 MHz) rotamers δ 4.55 (d, J 5.8, 2H), 7.45 (m,1H), 7.63 (t, J 6.1, 1H), 7.82 (m, 1H), 8.05(d, J 8.1, 1H), 8.56 (m,2H), 8.69 (d, J 6.4, 1H), 9.51 (s, 1H), 9.70 (s, 1H); Anal. Calcd forC₁₈H₁₂F₅N₃O+0.8 HCl: C, 52.67; H, 3.14; N, 10.24. Found: C, 52.53; H,3.38; N, 10.22.

EXAMPLE 305N-[2-chloro-4-(trifluoromethyl)benzyl]-N′-5-isoquinolinylurea

The title compound was prepared using the procedure described in Example61B using 2-chloro-4-(trifluoromethyl)benzylamine instead of4-cyanobenzyl alcohol. MS (ESI+) m/z 380 (M+H)⁺; MS (ESI−) m/z 378(M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 4.53 (d, J 5.8, 2H), 7.69 (m, 2H), 7.87(m, 1H), 8.06 (d, J 8.1, 1H), 8.56 (d, J 7.8, 1H), 8.63 (d, J 6.8, 1H),8.70 (d, J 6.8, 1H), 9.59 (s, 1H), 9.72 (s, 1H); Anal. Calcd forC₁₈H₁₃C₁₃ClF₃N₃O+1.3 HCl: C, 50.61; H, 3.37; N, 9.84. Found: C, 50.60;H, 3.42 N, 9.61.

EXAMPLE 306N-5-isoquinolinyl-N′-{1-methyl-1-[4-(trifluoromethyl)phenyl]ethyl}urea

The title compound was prepared using the procedure described in Example61B using 2-[4-(trifluoromethyl)phenyl]-2-propanamine instead of4-cyanobenzyl alcohol. MS (ESI+) m/z 374 (M+H)⁺; MS (ESI−) m/z 372(M−H)⁻; ¹H NMR (DMSO, 300 MHz) δ 1.67 (s, 6H), 7.67 (s, 4H), 7.82 (t, J8.1, 1H), 8.02 (d, J 8.1, 1H), 8.54 (d, J 7.8, 1H), 8.72 (d, J 6.8, 1H),8.87 (d, J 6.8, 1H), 9.65 (s, 1H), 9.77 (s, 1H); Anal. Calcd forC₂₀H₁₈F₃N₃O+1 HCl: C, 58.61; H, 4.67. Found: C, 58.62; H, 4.65.

EXAMPLE 307 N-[2-(4-bromophenyl)-2-hydroxyethyl]-N′-5-isoquinolinylurea

The title compound was prepared using the procedure described in Example61B using 2-amino-1-(4-bromophenyl)ethanol instead of 4-cyanobenzylalcohol.

MS (ESI+) m/z 388, 386 (M+H)⁺; MS (ESI−) m/z 386, 384 (M−H)⁻; ¹H NMR(DMSO, 300 MHz) rotamers δ 3.27 (m, 1H), 3.42 (m, 1H), 4.70 (m, 1H),6.82 (t, J 5.0, 2H), 7.38 (d, J 8.5, 1H), 7.56 (d, J 8.5, 1H), 7.81 (t,J 7.8, 1H), 7.98 (d, J 8.7, 1H), 8.29 (d, J 7.5, 1H), 8.50 (d, J 5.9,1H), 8.67 (d, J 6.4, 1H), 9.01 (s, 1H), 9.64 (s, 1H); Anal. Calcd forC₁₈H₁₆BrN₃O₂+2.35 TFA: C, 41.68; H, 2.83; N, 6.42. Found: C, 41.69; H,2.86; N, 6.43.

It is understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to be taken aslimitations upon the scope of the invention, which is defined solely bythe appended claims and their equivalents. Various changes andmodifications to the disclosed embodiments will be apparent to thoseskilled in the art. Such changes and modifications, including withoutlimitation those relating to the chemical structures, substituents,derivatives, intermediates, syntheses, formulations and/or methods ofuse of the invention, may be made without departing from the spirit andscope thereof.

1. A compound of formula (I)

or a pharmaceutically acceptable salt or prodrug thereof, wherein — isabsent or is a single bond; X₁ is CR₁; X₂ is CR₂; X₃ is NR₃; X₄ is abond; X₅ is N; Z₁ is O; Z₂ is NH; L is selected from the groupconsisting of alkenylene, alkylene, alkynylene, cycloalkylene,

—(CH₂)_(m)O(CH₂)_(n)—, and N(R_(Y)), wherein the left end of—(CH₂)_(m)O(CH₂)_(n)— is attached to Z₂ and the right end is attached toR₉; m and n are each independently 1-6; R_(Y) is selected from the groupconsisting of hydrogen and alkyl; R₁, R₃, R₅, R₆, and R₇ are eachindependently selected from the group consisting of hydrogen, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkyl, alkylcarbonyloxy, carboxy,carboxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, haloalkylthio,halogen, hydroxy, hydroxyalkyl, NR_(A)S(O)₂R_(B), —S(O)₂R_(B),—NZ_(A)Z_(B), (NZ_(A)Z_(B))alkyl, (NZ_(A)Z_(B))carbonylalkyl and(NZ_(A)Z_(B))sulfonyl, wherein Z_(A) and Z_(B) are each independentlyselected from the group consisting of hydrogen, alkyl, alkylcarbonyl,aryl, and arylalkyl; R₂ and R₄ are each independently selected from thegroup consisting of hydrogen, alkoxy, alkoxyalkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl,alkylcarbonylalkyl, alkylcarbonyloxy, carboxy, carboxyalkyl, cyano,cyanoalkyl, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl,haloalkylthio, halogen, hydroxy, hydroxyalkyl, —NR_(A)S(O)₂R_(B),—S(O)₂OR_(A), —S(O)₂R_(B), —NZ_(A)Z_(B), (NZ_(A)Z_(B))alkyl,(NZ_(A)Z_(B))alkylcarbonyl, (NZ_(A)Z_(B))carbonyl,(NZ_(A)Z_(B))carbonylalkyl, and (NZ_(A)Z_(B))sulfonyl; R_(A) is selectedfrom the group consisting of hydrogen and alkyl; R_(B) is selected fromthe group consisting of alkyl, aryl, and arylalkyl; R_(8a) is selectedfrom the group consisting of hydrogen and alkyl; and R₉ is selected fromthe group consisting of hydrogen, aryl, cycloalkyl, and heterocycle. 2.A compound according to claim 1 wherein L is alkylene; and R₉ is aryl.3. A compound according to claim 1 wherein R₁, R₂, R₅, R₆ and R₇ areeach hydrogen; L is alkylene; R₉ is aryl wherein said aryl is phenylsubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of alkoxy, alkyl, alkylsulfonyl, 1-azepanyl,1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen,methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl,1-piperidinyl, 4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl,4-thiomorpholinyl, and —NZ_(C)Z_(D); and Z_(C) and Z_(D) areindependently selected from the group consisting of hydrogen and alkyl.4. A compound according to claim 3 selected from the group consisting ofN-(4-bromobenzyl)-N′-1H-indol-4-ylurea;N-(3,4-dichlorobenzyl)-N′-1H-indol-4-ylurea;N-1H-indol-4-yl-N′-[4-(trifluoromethyl)benzyl]urea;N-1H-indol-4-yl-N′-[4-(trifluoromethoxy)benzyl]urea;N-[3-fluoro-4-(trifluoromethyl)benzyl]-N′-1H-indol-4-ylurea;1-(4-chloro-3-trifluoromethyl-benzyl)-3-(1H-indol-4-yl)-urea;1-(4-chloro-3-trifluoromethyl)-3-(1H-indol-4-yl)-urea; andN-[2-(2,4-dichlorophenyl)ethyl]-N′-1H-indol-4-ylurea.
 5. A compoundaccording to claim 1 wherein R₁ and R₂ are each independently alkyl; R₅,R₆ and R₇ are each hydrogen; L is alkylene; R₉ is aryl wherein said arylis phenyl substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of alkoxy, alkyl, alkylsulfonyl,1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio,halogen, methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl,phenyl, 1-piperidinyl, 4-methyl-1-piperidinyl, pyridinyl,1-pyrrolidinyl, 4-thiomorpholinyl, and —NZ_(C)Z_(D); and Z_(C) and Z_(D)are independently selected from the group consisting of hydrogen andalkyl.
 6. A compound according to claim 5 that isN-(4-bromobenzyl)-N′-(2,3-dimethyl-1H-indol-4-yl)urea.
 7. Apharmaceutical composition comprising a therapeutically effective amountof a compound of formula (I) according to claim 1 or a pharmaceuticallyacceptable salt thereof.
 8. A method of treating a disorder wherein thedisorder is ameliorated by inhibiting vanilloid receptor subtype 1 (VR1)receptor, and wherein the disorder is selected from the group comprisingpain, bladder overactivity, urinary incontinence and inflammatoryhyperalgesia—in a host mammal in need of such treatment comprisingadministering a therapeutically effective amount of a compound offormula (I) according to claim 1, or a pharmaceutically acceptable saltthereof.
 9. The method of treating according to claim 8, wherein thedisorder is bladder overactivity.
 10. The method of treating accordingto claim 8, wherein the disorder is urinary incontinence.
 11. The methodof treating to claim 8, wherein the disorder is pain.
 12. The method oftreating to claim 8, wherein the disorder is inflammatory hyperalgesia.